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Human-Centred Design in Biopharma: Need of the hour

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Pharma Focus Asia

The document discusses future prospects and challenges for biotherapeutics. It begins by defining biotherapeutics as products produced using living cells or organisms, such as recombinant hormones, vaccines, monoclonal antibodies, growth factors, and gene and cell therapies. It then contrasts biotherapeutics, biosimilars, and generics. The document outlines the complex manufacturing process for biotherapeutics and challenges in characterizing their large, complex structures. It concludes by discussing switching and interchangeability studies required to demonstrate a biosimilar is as safe and effective as the reference biologic.

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Issue 29 2017 www.pharmafocusasia.com Wearables in Clinical Trials Where we are & where we are going Patient Recruitment in Asia Reducing the clinical burden
kromasil@akzonobel.com India & Middle-East: +91 22 2778 7338 Worldwide: +46 31 58 70 00 www.kromasil.com For the purification of • Peptides • Small proteins • Oligonucleotides • Small molecules HPLC columns and bulk media for analysis and API purification by industrial-scale chromatography High performance spherical silica
Foreword Prasanthi Sadhu Editor market. Design thinking enables organisations to bring-in cross-departmental innovation, deliver value-added solutions and unleash market opportunities. HCD brings together company leadership both strategic and operational, stakeholders that work in a collaborative environment with uniform goals and unified approach to solutions. This process includes defining roles and responsibilities for all those involved. By integrating human-centred research, the molecular development process benefts from parallel human-centred research throughout the discovery and development phase. This also helps in increasing the productivity by choosing the most useful potential medicines among many alternatives and help articulate real value to users for a given medicine. By supporting human-centred research, R&D organisations can signifcantly augment their tools for guiding personalised medicine and create robust portfolios of products that users strongly value. In the cover story of this issue, authors Andrew Parsonsand Susan Cruse suggest that a human-centred experiential learning process to develop leaders, managers, and employees is quintessential for success. Paying attention to the ‘human’ will enable development of solutions for addressing leadership challenges. If we hope to create something of lasting value, we need to start with what people want — not just with what’s technically possible! IDEO, a global design firm. Innovation and technology advancements play a key role in product design and development, but it is imperative that companies bring in a human-centred approach. The advent of new technologies such as virtual reality, augmented reality, digital assistant etc. throws light on integrating those into human lives for better application and experience. Think of a Fit-bit – it tracks one’s physical activity, sleep and throws inputs on areas of improvement thus helping an individual stay physically active. Human Centred- Design (HCD) is a methodology that focuses on the people that you serve and places them at the center of design and implementation. HCD combines research and insights with business and technology requirements to produce the best output. It is indeed more relevant for the life sciences and healthcare sectors as the onus is on producing effective drugs and care. From the pharma industry perspective, design thinking could be using design to come up with ideas to effective connect with and offer care to patient. A study conducted by the Drug Information Association (DIA) in collaboration with the Tufts Center for the Study of Drug Development (CSDD) indicates more than 65 per cent of pharma and biotech companies are inclined to invest in drug development through patient centric initiatives. As the demand for patient-centred drug development and service continues to rise, a human centred approach could be the differentiator for companies in the Human-Centred Design in Biopharma Need of the hour
2 Pharma Focus Asia ISSUE - 29 2017 Contents Strategy 06 Future Prospects of Biotherapeutics and Challenges Ambikanandan Misra, Faculty of Pharmacy The Maharaja Sayajirao University of Baroda Clinical Trials 26 Patient Recruitment in Asia Reducing the clinical burden David Yoshii, Senior Director, Global Site Solutions PAREXEL International 30 Low Rates of Stroke and Major Bleeding with Rivaroxaban Confirmed by Global Study XANTUS pooled results study John Battersby, Medical Writer, Bridges Publishing Pte Ltd 36 Wearables in Clinical Trials Where we are & where we are going Xavier Flinois, President, PAREXEL Informatics Research & Development 40 Merging Technology Transfer with Knowledge Translation Academic to industrial research Vivek Dave, Sachdev Yadav, Harshavardhan ML Yadav Isha Mehta Department of Pharmacy, Banasthali University 48 Creating the Perfect Capsule Choosing the right shell excipient for your formulation challenges Bjorn Vergauwen, Principal Scientist, Rousselot Manufacturing 52 The Rise in Sterile Manufacturing A focus on containment Christian Dunne, Global Product Manager ChargePoint Technology Information Technology 58 Take a Pass on the 3pm Samples Steve Madden, Software Product Manager Mass Spectrometry Agilent Technologies 62 Books The Human-Centred Biopharma Organisation Andrew A Parsons, Reciprocal Minds Limited Susan M Cruse, Leadership Mastery Limited COVERSTORY 18 48 30
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4 Pharma Focus Asia ISSUE - 29 2017 Editor Prasanthi Sadhu Editorial Team Debi Jones Grace Jones Art Director M Abdul Hannan Product Manager Jeff Kenney Senior Product Associates David Nelson Peter Thomas Sussane Vincent Product Associates Austin Paul Ben Johnson Veronica Wilson Circulation Team Naveen M Nash Jones Sam Smith Subscriptions In-charge Vijay Kumar Gaddam Head-Operations S V Nageswara Rao AdvisoryBoard Frank Jaeger Regional Sales Manager, Metabolics, AbbVie, USA Douglas Meyer Senior Director, Aptuit Informatics Inc., USA Christopher-Paul Milne Director of Research, Tufts Center for the Study of Drug Development, Tufts University, USA Alan S Louie Research Director, Health Industry Insights an IDC Company, USA Georg C Terstappen Director and Head of Biology, Neuroscience Discovery AbbVie Deutschland GmbH und Co. KG, Germany Sanjoy Ray Director, Strategic Alliances & Health Innovation Merck, US Rustom Mody Senior Vice President and R&D Head Lupin Ltd., (Biotech Division), India Phil Kaminsky Chair, Department of Industrial Engineering and Operations Research University of California, Berkeley, USA Neil J Campbell President & CEO, Helomics Corporation HealthCare Royalty Partners University of Liverpool, UK Laurence Flint Head Clinical Research Cough, Cold & Respiratory Disease Novartis Consumer Health, Inc., USA Kenneth I Kaitin Director and Professor of Medicine, Tufts Center for the Study of Drug Development, Tufts University, USA Ochre Media Private Limited Media Resource Centre,#9-1-129/1,201, 2nd Floor, Oxford Plaza, S.D Road, Secunderabad - 500003, Telangana, INDIA, Phone: +91 40 4961 4567, Fax: +91 40 4961 4555 Email: info@ochre-media.com Pharma Focus Asia is published by © Ochre Media Private Limited. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, elec- tronic, photocopying or otherwise, without prior permission of the publisher and copyright owner. Whilst every effort has been made to ensure the accuracy of the information in this publication, the publisher accepts no responsibility for errors or omissions. The products and services advertised are not endorsed by or connected with the publisher or its associates. The editorial opinions expressed in this publication are those of individual authors and not necessarily those of the publisher or of its associates. Copies of Pharma Focus Asia can be purchased at the indicated cover prices. For bulk order reprints minimum order required is 500 copies, POA. www.pharmafocusasia.com | www.ochre-media.com A member of Confederation of Indian Industry In Association with Strategy
It takes a unique blend of expertise to deliver the right results From clinical development to commercial production At Vetter, we look at your product from every angle. And help you find answers that make a difference in efficiency, productivity, safety, quality, and growth. From initial process design through high-speed fill and finish, learn how a partnership with Vetter will keep your product moving smoothly towards success. More than 35 years of experience in aseptic filling Expertise with many compound classes, including biologics Highly trained experts in key technical areas Integrated life cycle management Innovative drug delivery options State-of-the-art cGMP manufacturing Excellent global regulatory support Vetter Development Service Vetter Commercial Manufacturing Vetter Packaging Solutions US inquiries: infoUS@vetter-pharma.com • Asia Pacific inquiries: infoAsiaPacific@vetter-pharma.com • Japan inquiries: infoJapan@vetter-pharma.com • EU and other international inquiries: info@vetter-pharma.com Answers that work www.vetter-pharma.com
6 Pharma Focus Asia ISSUE - 29 2017 Advancements in the biotechnology have presented pharmaceutical manufacturing industries biotherapeutics which are promising as potential future therapeutics. Diverse categories of biotherapeutics are coming into the market which range from monoclonal antibodies, growth hormones and cytokines to vaccines. Present topic will cover the future prospects and challenges to the biotherapeutics. Ambikanandan Misra, Faculty of Pharmacy, The Maharaja Sayajirao University of Baroda B iotherapeutics or biological products are generally produced using living cells or organisms (recombinant DNA technology, controlled gene expression and antibody technologies). It may be manufactured using biotechnology derived from natural sources or produced synthetically. Recombinant hormones, vaccines, monoclonal antibody based products, growth factors, blood products and advanced technology products (gene and cell therapy biological products) are few of the biotherapeutics. According to definition of the PHS (Public health service) act of USFDA, biological products are defined as a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesised polypeptide), or analogous product which are applicable to the prevention, treatment, or cure of a disease or condition of human beings. Proteins Future Prospects of Biotherapeutics and Challenges Strategy
7w w w . p h a r m a f o c u s a s i a . c o m Strategy Gene screening & vector insertation Host cell expression & cell culture Protein production and purification Formulation & Development and Analysis Storage & handling are classified as drugs as well as biologics in USFDA but proteins are regulated as a biological product, except any chemically synthesised polypeptide, under the BPCI act. Difference between Biologics, Biosimilars and Generics The generic version of biolog- ics are known as biosimilars in Europe, Similar biologics in India, follow-on Pharmaceutical in USA and Japan, subsequent entry biologics in Canada, and biocomparables in Mexico. The origin of the terminology lies
8 Pharma Focus Asia ISSUE - 29 2017 Parameters Characterisation technique Primary sequence (peptide map andamino acid sequence analysis), immunogenicity (immunoassay) other identity indicators IE, HPLC, gel electrophoresis Potency Cell-based bioassay, gene expression bioassay, ADCC, CDC Conformation Near/far UV circular dichroism spectroscopy, Fourier transform infrared spectroscopy, X ray crystallography and differential scanning calorimetry Glycosylation onosaccharide composition analysis, oligosaccharide profile, CE, LC-MS, MS/MS, ESI, MALDI-TOF Phosphorylation Peptide mapping with MS Truncation SE-HPLC, gel electrophoresis, AUC, peptide mapping with MS, RP HPLC Glycation Peptide mapping with (MS, HPLC), methylation, isomerisation (RP HPLC) Pegylation HPLC, CE Aggregation SE-HPLC, gel electrophoresis, Light scattering and AUC Oxidation Peptide mapping with MS Deamidation Capillary IEF, peptide mapping with MS, and CEX-HPLC, C-terminal lysine (capillary IEF, peptide mapping with MS, and CEX-HPLC), misfolds (RP-HPLC) Host cell proteins ELISA, DNA, endotoxin (Limulus amoebocyte lysate assay) Binding Cell assays, spectroscopy, ELISA Biological activity Cell assays, animal models Abbreviations: IE, ion exchange; HPLC, high performance liquid chromatography; ADCC, antibody-dependent cell-mediated cytotoxicity; CDC, complement-dependent cytotoxicity; CE, capillary electrophoresis; LC–MS, liquid chromatography–mass spectroscopy; MS/MS, tandem mass spectrometry; ESI, electrospray ionisation; MALDI-TOF, matrix-assisted laser desorption/ionisation time of flight MS; AUC, analytical ultracentrifugation; CEX, cation exchange; IEF, isoelectric focusing; SE, size exclusion; RP-HPLC, reverse phase HPLC; ELISA, enzyme-linked immunosorbent assay; QSE, quality safety and efficacy. in the loss of patent protection of first generation innovator biologics in last decades. Biologics are at least 1000 times larger than conventional drugs or generic drugs in size containing hundreds of amino acids joined by peptide bonds to form a polypeptide. It is very difficult to establish reproducibility for biosimilars whereas reproducibil- ity can be easily achieved by generics or small molecules conventional drugs. Biologics, biosimilars and generics are needed to exhibit comparabil- ity, biosimilarity, and bioequivalence respectively. The non-medical switch- ing is not allowed in biologics and biosimilars whereas it is allowed in generics. Biopharmaceutical produc- tions methods are more complex than chemical production methods so production cost automatically goes higher than generic counter- parts. Although the goals are same — to treat the disease—biotherapeutics and generics differ substantially in ways that might affect innovation, safety, costs, clinical adoption, patient access, and pricing. Manufacturing of Biotherapeutics The stable Biotherapeutics consist of Primary (amino acid sequence) and Secondary structures (α-helix and β-sheets) which are folded to form 3D-Tertritary structures that is converted into quaternary structure. The biological activity can be attributed to glycosylation and sialylation. The characterisation remains the challenge for biotherapeutics due to larger size and structural complexity. A typical biotherapeutics production involves following steps: The methods of biotherapeutics characterisation are divided into quality, safety and efficacy of product which requires clearance by regulatory body and further comparability exercise. There is a significant improvement in formulation of biotherapeutics and characterisation of the products due to recent guidelines on the International Conference on Harmonisation Q8 Strategy
9w w w . p h a r m a f o c u s a s i a . c o m on pharmaceutical development and the roll-out of the Quality by Design and Process Analytical Technology, comparability of biotechnological / biological Products subject to changes in their Manufacturing process Q5E and quality of biotechnological products: stability testing of biotechnological / biological products Q5C. There are methods for characterisation of biotherapeutics as mentioned in the table. Switching and Interchangeability in Biosimilars Reference product biologics and their biosimilars are very important treatment options for multiple diseases and have the potential to expand the possibilities for our patients. Switching studies evaluate all the parameters change with exposure to interchangeable product with reference one. The main purpose of this study is to demonstrate the risk in terms of safety or diminished biological activity between interchangeable molecules. As per FDA a product is interchangeable with biosimilars, if the manufacturer proves that it is expected to produce same clinical result in same patient only is product considered as safe. Comparability studies are performed between a biosimilars and its reference product, but studies between one biosimilars and another are not done; two separate biosimilars may have been compared to the same reference but not between themselves. Challenges in Development of Biosimilars European Medicine Agency (EMEA) has first issued guidelines defining biosimilar approval pathway which has been adopted and/modified by several countries. Guidelines issued by WHO are almost similar to EMEA guidelines. However, similarities in the guidelines is just the tip of the iceberg, and there is an intense need for streamlining the standards. Furthermore, companies are suspending the development of biosimilars at clinical stages, hesitating to conduct single and global development programmes due to the changes in the IP rights, evolving guidelines (many countries are changing their guidelines abruptly as the understanding and definitions of biosimilarity, interchangeability, substitution etc. evolve), unknown patient-to-patient variability between the biosimilar and reference biologic in Phase I/II studies, large variability encountered in PK/PD studies, safety, efficacy and immunogenicity profiles due to manufacturing quality, uncertainty in Phase III trials (whether to consider the Phase III trials as non-inferiority trials or bioequivalence trials) etc. Many countries require that the reference biologic be approved /licensed/ marketed in the country. So, it becomes very difficult for the companies to target other countries using same biosimilar, as it would raise the questions due to large number of quality comparisons to be established, number of different toxicology and clinical studies to be performed. High development costs force companies to focus first on developed nations with large market size which will delay/limit development of biosimilars Strategy 2008 No guidelines• on bio similar in the U.S. Debate on key• issues Pathway• passed as part of the ACA 2010 2009 Implementation• of the Biologics Price Competition and Innovation Act 2012 Draft guidence• issued from U.S. FDA with Clarity on• biosimilar approval pathway 2014 Purple Book• published Sandoz and• Celltrion field biosimilar candidate applications for regulatory approval 97 biosimilars• in development 2013 $42B• Total global sale Current trends in biosimilars
10 Pharma Focus Asia ISSUE - 29 2017 Strategy AuthorBIO Ambikanandan Misra is Professor of Pharmacy at Faculty of Pharmacy at The Maharaja Sayajirao University of Baroda. He has been associated with the field of pharmaceutical sciences for more than 38 years. 42 PhD and 128 Master students have completed their dissertation under his guidance. He has 7 books, 40 book chapters and 156 peer reviewed publications in reputed journals. He has filed 29 national and international patents out of which 8 have been granted so far. Source of RWD United States European States Approval Procedure Approval is based on the information indicative of the biological product is highly similar along with no meaningful discrepancy in their safety, potency and / or the purity to that of the reference biological product (1) Approval is based on by comparing the biosimilar product with its reference biological product demonstrate that there are no significant changes between them (Applicable clinical data necessary to compare with the inventor) (2) Naming Manufacturer and FDA determines the naming of biosimilar product (3) Approving body of the individual member states determines to name of the biosimilar product (3) Labeling A statement has to be written on the product that it is a biosimilar for specified indication(s) as well as administration route(s), and if biosimilar is interchangeable with reference biological product (1) A clear indication on all the biosimilar products with the black symbol and standardised descriptive statement (4) Interchangeability FDA determines the interchangeability of the biosimilar product to the reference biologic based on the optional evaluation (5) EMA declines interchangeability of the biosimilar product to the reference biologic (6) Automatic Switching Executed by state laws (7) Executed by individual member states (6) Pharmacovigilance Endorsements Regulation and the awareness of the product specific post- marketing safety monitoring by FDA (1) Product name and Batch number are the identities of all biologics (4) Regulatory frameworks in biosimilars in EU & USA medicines. The cumulative market potential may reach beyond EUR 100 billion in next five years. There are at least 50 distinct biosimilars in pipeline and will be delivered successfully in next five years. Biosimilars can bring improvements to patient outcomes by providing more treatment options to physicians and reducing the need for rationing. Conclusion Though adopted and evolved from similar background, a large amount of discrepancies exists between regulatory guidelines being followed in different countries. There is a mandate for harmonising the guidelines at global level which will ease the biosimilars product manufacturing in several countries enabling the companies to globally market their biosimilar products. There is a potential opportunity for biopharmaceutical companies for low-cost manufacturing in semi- regulated and non-regulated markets. Companies need to review and follow all quality, safety, and efficacy parameters of different countries and revising the development plan for biosimilars from time to time addressing the country-by country differences. India is gearing up with the companies that are adopting guidelines more in line with EU and USA. Soon, more Indian companies will get through the rigid approval framework including refined requirements of non-clinical and clinical evaluations; India is going to make its stance as a provider of low-cost biosimilar products. for countries with smaller markets. All of this mandates that the biosimilar guidelines evolve and be streamlined as soon as possible. Until then, there is no option other than to consider the specified pathways of each country. Streamlining will surely take time; but once done, there will be a step-wise approach for biosimilar authorisation /marketing in several countries. Thorough and defined quality characterisation tests, non-clinical studies, extent of clinical studies and standards for reference biologics will be specified which will help extrapolation of data from one indication to other approved indications of innovator product. It will also resolve the differences in nomenclature that may cause multiple revisions of clinical trials and marketing authorisation applications for consistency with guidelines and regulations. The Potential of Biosimilars A number of key biologics are going off patent by 2020, thus there is a huge potential for Biosimilar version of these
Strategy
12 Pharma Focus Asia ISSUE - 29 201712 Pharma Focus AsiA ISSUE - 29 2017 How Best to introduce Medical Devices Class II Products into the Chinese Market How best to introduce medical devices class II products into the chinese market? Many Pharma companies are still bothering from China regulations. Having a partner who understands the opportunity and competitive environment of the Chinese marketplace is absolutely essential and can be the difference between success and failure. Phillips-Medisize explains the work to bring a rapid development of a variable dose pen injector in China through regulatory approval. Bill Welch, CTO, Phillips-Medisize Finding the most appropriate foreign manufacturing partners for Chinese companies in the medical devices marketplace involves complex studies and background research for suitable partnership candidate companies into a number of key issues. Foreign drug companies needtounderstandthismarket’schallengestocapitalize on the opportunities and obvious long-term benefits for both parties. By gaining an in-depth knowledge into the country’s regulatory body, an organization can leverage this experience to both advance its product and to create a solid and sustainable foundation for an expanding manufacturing strategy in China. With a sales volume of $ 48.5 billion in 2015 China is one of the world’s largest and fastest growing medical device markets. This represented a Compound
13w w w . p h a r m a f o c u s a s i a . c o m 13w w w . p h a r m a f o c u s a s i a . c o m Annual Growth Rate (CAGR) of some 22.3 percent between 2010 and 2015. Today, China is the world’s 2nd largest medical device market with overall healthcare expected to reach $ 1.3 trillion by the end of 2018. This market is expected to continue to grow strongly, with pharmaceutical expenditure expected to increase at a rate of almost 70 percent over the next five years.Finding the most appropriate reliable long- term global partners is an essential part in securing ongoing sustainable growth in that sector to satisfy demand. Currently, approx. 300 million Chinese patients are suffering from chronic diseases alone; this number is boundtoriseovertime.Suchdiseasesincludediabetes and many other conditions requiring treatment with medical devices for diagnostics and drug delivery. And this is just the home market – not taking product exports into consideration. Only the most advances high-tech organizations with a global presence producing innovative medical devices can offer the multi-faceted requirements in such a complex market place. The principal criteria include: 1. Speed of innovation , passage time to market – critical assets assessment to reach market viability 2. From Part to Market 3. Product Approval and Registration–knowledge and experience in and speedy execution of As a contract manufacturing organization (CMO) and a contract development and manufacturing organization (CDMO), Phillips-Medisize is one such forward-lookingcompanysatisfyingthecriticalfactors relevant for the vast Chinese markets in the Medical Devices Class II sector. More than just a molder, the company specializes in design through distribution services and has created an environment focused on high quality and adherence to rigorous time-to- market schedules. Furthermore, the company has had a design manufacturing center near Shanghai for the past three years. A newly added medical devices registration operation has been given to the medical device production facility that has Good Manufacturing Practice (GMP) from the China Food and Drug Administration (CFDA). This means that the paths – innovation and part to market – have already been cleared to a great extent. Phillips-Medisize already has in-depth insight into the many regulations, guidelines, protocols, procedures and codes of practice for Medical Devices Class II products and their timely implementations are the cornerstone of a long-lasting productive partnership. Last, but not least, the ability to recognize the unique market trends within China are part of the company’s strength. This gives this organization a vitally important competitive edge. In addition, familiarity with product testing and the final product registration are an important part of what Phillips-Medisize can offer potential partners in China. When it comes to Medical Devices Class II products, the Phillips-Medisize variable auto-dose pen injector, insulin pen, is a prime example of the classification. 1. Speed of Innovation The time between initial concept of the product or product development must be kept to an absolute minimum and without compromising fundamental part of the process. Here, the knowledge of all vital segments of state-of-the-art technology is, at the very best, a routine part of any appropriate company’s remit. Suitable partners must possess the critical assets essential to satisfy Chinese manufacturers. Commercial viability and market maturity are familiar phrases to any suitable candidate. Criteria include global presence, in-depth market knowledge in the guest country, fully trained design, development and implementation personnel able to work with its customers to deliver advanced automated assembly and quality control technologies on a long-term basis, which reduce manufacturing cost while, in tandem, improve quality. 2. From Part to Market Serving such a large, fast growing market such as China, and allowing for potentially prolonged approval times requires that device producers keep the time to market readiness for new products to an absolute minimum without compromising the process. Advertorial
14 Pharma Focus Asia ISSUE - 29 201714 Pharma Focus AsiA ISSUE - 29 2017 Insteadofaconventional‘linear’productdevelopment life cycle with manufacturing development and manufacturing stages after a large part of the product development phases has been completed, Phillips-Medisize has considerably shortened lead times to market by bringing forward two manufacturing stages to start and run parallel with the product proof of concept stage of development. Thus the concept development stage has become a concept and manufacturing development stage and the validation stage includes both product development and manufacturing elements. By adopting a systems engineering approach at an early proof-of-concept stage, the company also aims at reducing financial and other risks in efficient device development to meet more advanced technical requirements, as well as ensuring that required devices reach the market within agreed schedules. This is achieved by paying particular attention to each individual component contained within the drug delivery systems, as well as to the method by which the components, sub-systems and complete systems are fully integrated and work effectively with each other. The systems engineering approach is more robust than with linear product development, as it requires some engineers dedicated to systems and others to sub-systems development. For example, Phillips-Medisize states that although this involves higher up-front early development stage costs than with linear product development, it saves other expenses later on, e.g. if the need arises to trace back the cause for a device not properly functioning at a later stage in development or marketing. The potential higher up-front development costs are minimized by integrating Design for Manufacture (DFM) and Design for Assembly (DFA), as 80 percent of product cost and quality are often determined during the first 20 percent of the product development cycle. Manufacturing strategy must be fully aligned with device strategy in order to avoid end stage changes which may compromise stakeholder requirements or program feasibility. 3. Product Approval and Registration Bill Welch, Chief Technology Officer at Phillips-Medisize, explains the registration and approval process: Any serious contender, contract development and manufacturing organizations (CDMO), keen to enter the Chinese medical devices market, must be totally familiar with the time-consuming regulatory approval procedure. Again, taking the insulin pen as an example, the initial step to be taken is the appointment and retention of a qualified agent based in China who will coordinate registration with the CFDA, also known as the State Food and Drug Administration (SFDA) or simply State Drug Administration (SDA).
15w w w . p h a r m a f o c u s a s i a . c o m 15w w w . p h a r m a f o c u s a s i a . c o m This approach applies in a formal review process for the single device, the device and the drugs it delivers or in parallel reviews for the device and drug. Products should be treated both as the sum of the constituent drug and delivery device parts, but also as a complete treatment system. All the different routes along the registration and approval path influence the time to market speed. They are equivalent to speed control bumps along a motorway impeding rapid progress to a successful conclusion. Documents submitted in approval applications should include not only data on product performance, but also on, for example, risk analysis and technical requirements, animal trials, biocompatibility, bio safety, drug expiry and package as well as software aspects. The review process takes into account whether the device is produced in China, requiring a Device Manufacturing Permit (DMP), or imported from abroad, either in part or as a whole. Domestic Chinese and international approval status is taken into account, as well as whether production takes place as a certified GMP process and, in the case of a drug, whether it already has an import license. Authorization is granted if already approved in the producer’s home country. It is less complex to introduce new products into the Chinese market if they are produced in China, specifically or mainly for the Chinese market. Failing that, products should, at least, be either clinically trialed in their country of origin or supported by data showing that a medical device is ‘substantially equivalent’ to those already produced in and, therefore, approved in China. The local agent submits the device at a medical device evaluation center for approved by the CFDA and at provincial FDA locations, as both these bodies are responsible for regulations and guidance. They may well request additional clinical trials if new first of its-kind devices are submitted. Producers should have a well-developed clinical strategy and have backing of, for instance, risk- benefit analyses by an ethics committee in the EU or an equivalent Institutional Review Board (IRB) in the USA, which formally approves, monitors and reviews biomedical and research involving humans. The registration partner can encounter challenges during the approval process, such as substantial regulatory changes or newly introduced registration and certification requirements. It is therefore diligent to conduct gap analysis, to compare actual and desired performance, as a basis for timely corrective action. Information should be submitted in an easily understandable form and available in the appropriate local Chinese language at all levels. CFDA nationally and FDA at both provincial and city levels are involved with quality system inspection and post-market surveillance, the FDA city level for manufacturing site licensing. The entire process can be challenging as FDA officials are known to be inundated with drug and delivery device applications over past years. The CFDA receives over 10,000 new drug applications each year, but is limited by its review capacity of 5,000 to 6,000 pa. This has resulted in a backlog, estimated currently at around 21,000 submissions. The result is that foreign companies face potentially longer waiting times for approval than Chinese companies. In addition, approval times for new products can take longer than renewal approvals for existing products, some 20 percent or so longer for Class III devices and between 15-25 percent for new drugs and biologics (genetically-modified proteins derived from living entities). Advertorial Longer and more costly registration times may also be expected due to medical device classification in China according to CFDA’s SDA Order Number 15 differing significantly from EU and US classifications. For example, a Class II device in the USA or a Class IIa/IIb device in the EU could be considered Class III in China.
16 Pharma Focus Asia ISSUE - 29 201716 Pharma Focus AsiA ISSUE - 29 2017 FDA offices are not only suffering from staff shortages thus increasing work load for officials, they are also required to cope with the decentralized regulatory structure, absence of a common IT infrastructure and a lack of consistent policies which hinder effective communication between the various FDA offices. There is also limited ability to track national and global databases for adverse events, unlike tracking procedures that have become well established in the EU and North America. Apart from CFDA and FDA offices, establishment of contacts and a local interface with the Centre for Medical Device Evaluation (CMDE), the Centre for Drug Evaluation (CDE) and the General Administration of Quality Supervision, Inspection, and Quarantine (AQSIQ) are also advisable. This pressure on the regulatory and approval system is a development mainly as a result of the size and speed of growth of the Chinese healthcare market. Variable Dosing Prospects Medical device research consultancy Quality Invention (QI LLC) was involved with Phillips-Medisize in the insulin pen development. According to them, the consultancy’sprimegoalisthedesignanddevelopment of medical devices to address combination product challenges in the pharma industry. The consultancy is headed by Dr Min Wei, a registered patent agent, who not only holds a PhD in Material Science, but also MSc qualifications in Polymer and Computer Sciences, supplemented by a Master’s degree in Business Administration (MBA). Unlike variable-dose auto-injectors, Wei points out that fixed-dose auto-injectors do not address individual personalized medication needs for multiple doses, fail to meet different dosing needs of adults and children, present challenges to registration and compliance as combination products (combination of the drug and its delivery device), and are expensive if integrated into adaptive clinical trials. More usability data can be collected in clinical trials with variable-dose auto-injectors and they have greater dosing accuracy than conventional vial and syringe dosing. He states that variable-dose auto-injectors can be easily adopted for use with medicines that are already available in graduated pre-filled syringes, from e.g. Amgen, Genetech, Novartis and Sanofi, enabling a smooth transition into variable dosing for both patients and their doctors and other medical staff. According to Wei, the medicines so far available in this form and already administered in millions of units per year are Epoetin alfa (Epogen), Filgrastim (Neupogen), Enoxaparin sodium (Lovenox) and Methotrexate. But Relistor, Sumatriptan succinate, Invega, Stelara, Procrit and Humira are additional medicines calling
17w w w . p h a r m a f o c u s a s i a . c o m 17w w w . p h a r m a f o c u s a s i a . c o m A u t h o r BIO Bill Welch has over 25 years of contract design, development and manufacturing experience, primarily serving customers in the drug delivery, health technology and diagnostics markets. In his current capacity as Chief Technical Officer at Phillips-Medisize, he leads a global, over-600 person development, engineering, tooling, programme management and validation organisation. Bill has been with Phillips-Medisize since 2002. for variable dosing and which could also be efficiently dosed by a variable does injector. Wei adds that many more are in the pipeline. Due to greater fear of injections than adults, children (pediatric patients) have the greatest need for variable dosing, the quantity being determined by body weight or surface area. Bill Welch is of the opinion that there is evidence that adaptiveclinical trials (CTs), those where multiple formulations can be evaluated and where there is a prospect of modification later on in the trial. They are gaining in popularity, as they shorten study duration andreducecosts,improvechancesofsuccess,andare ethically superior. Most importantly, Welch maintains that variable-dose auto-injectors provide the flexibility to run adaptive CTs without design modifications or in excessive production quantities. He illustrates this with an example where a CT with a variable-dose auto-injector can reduce drug quantity needed by a factor of seven, compared to running the CT with fixed dosing, resulting in estimated cost savings of $12 million, based on seven doses per week over 52 weeks, with 400 patients, and assuming a $100 preparation cost for each CT drug unit. He refers to data in a report by K. Spenceret and others in the Journal of Diabetes Science & Technology; issue 6:1296, 2012. Typical Auto-Injector Design A typical variable-dose auto-injector is a graduated pre-filled syringe, which can be seen by the user via a viewing window in the pen housing. The user rotates a dialing cap on the top of the pen, so that it moves along a dosing scale marked on the pen body for the correct dose required. The user then removes the bottom cap and needle shield, removing the dialing cap to expose the actuation button, before placing the bottom of the injector against the area to be injected. Pressing the actuation button then triggers auto-injection. When the pen is removed from the injected area the user is required to replace the needle shield, or sharps cover, for safety reasons. Welch points out that such pens can be designed as a platform that enables 1mL long or 2.25mL variable- dose auto-injectors to be easily transformed into fixed- dose disposable and fixed-dose reusable versions without complete redesign, as the housing and many other components are identical across the entire platform, also when, for instance, a fixed-dose auto- injector is supplied with a connectivity function. This means that different types of auto-injectors can be produced on one assembly line. By gaining in-depth knowledge of the country’s regulatory procedures, an organization can leverage this experience to both advance its product and to create a stable foundation for a global expansion strategy in China and beyond. This means that proven success in China serves as a valuable marketing tool and the experience and knowledge can be invaluable for medical device manufacturers when entering other countries across the globe. The Chinese medical device market was recently valued at $27.7 billion and is projected to grow to an estimated $50.8 billion in 2020. Given the growth in medical device sales and the predicted rise in population in China at a rapid pace, this is undoubtedly a market that medical device companies are keen to enter in order to take advantage of the obvious and exciting opportunities. Advertorial
18 Pharma Focus Asia ISSUE - 29 2017 The biopharmaceutical industry is in continual change. Increased competition and diversity in business models creates a leadership challenge of sustaining growth and performance. To address this challenge, we outline a focus on Human Centred Organisations, with Leaders creating meaningful and engaged work environments to maximise performance sustainably. Andrew A Parsons, Reciprocal Minds Limited Susan M Cruse, Leadership Mastery Limited COVERSTORY Strategy The Human-Centred Biopharma Organisation
19w w w . p h a r m a f o c u s a s i a . c o m Strategy T o maximise performance, it is time to put the human in the centre of the complex, multicultural and dispersed ecosystem of biopharma innovation. The Challenge of Sustainable Growth - The Current Scenario The pharmaceutical industry has changed dramatically over the past 10 years. Despite a range of merger and acquisitions within large companies, the industry has grown in the number of companies selling products within the market. Comparing 2003 to 2015, the global industry has grown 41per cent in terms of revenue, 53 per cent in terms of R&D spend with a 100 per cent increase in clinical projects. Organisationally, the dispersed nature of the sector supports increased number of deals resulting in merger and acquisitions or IPO. The industry is therefore becoming increasingly fragmented and competitive in terms of revenue and organisational autonomy. Against this backdrop of increased fragmentation, it is apparent that successful projects and products remain elusive. The cost of development and easy access to medicines is a persistent issue that regulatory agencies and industry professionals are increasingly aware. There is an inherent tension within the system between the high levels of failure, the costs involved in development and commercialisation and the needs of public and private healthcare providers. Big Pharma has consequently adapted its strategy with wider global networks of research and development across hubs and a focus on the emerging markets. The
20 Pharma Focus Asia ISSUE - 29 2017 dispersed and global nature of the business has resulted in reductions within the knowledge base of discrete organisations and a drive to collaborate and gain expertise and know how from collaborators. A recent academic review highlighted key areas of collaboration including sharing and learning at organisational and team levels, and access to infrastructure and management expertise with appropriate governance control points of projects. These macro level changes in the pharma sector are evidence of some dramatic changes in operational business models. The days of large fully integrated pharmaceutical companies with depth and breadth of R&D projects and finances appear long gone. No doubt the model will continue to develop further over the next 10 years. The Leadership Challenge At a more specific or micro level of leaders and managers within individual companies, these macro level changes create some difficult challenges. Some key issues include how to create impact in decision making when you may work virtually or remotely? How to ensure effective and efficient communications across cultural boundaries and how to create engaged and productive teams and collaborations? There are no simple answers to these questions. We often focus on how to better use technologies and information. However, there are other approaches commonly used to ensure the most productive interface between people and what they do. In this article, we aim to raise awareness of human factor approaches and outline some pull and push approaches to ensure people can operate at their best, especially in the fast paced, multicultural, and global biopharma industry of today. What are Human Factors? Human factors encompass a professional science often known as ergonomics. It relates to the understanding of interactions among humans and other elements of a system. Human factors research has been applied across high- hazard sectors to develop safe practices that not only anticipate, but also mitigate, human error. Within the U.K. NHS, the importance of human factors has been highlighted and identified as an avenue for collaboration between disciplines providing key benefits in the utilisation of people, their needs and containing costs. Human-Centred Organisations In 2016, some guiding principles were developed by the International Standards Organisation (ISO) for developing human centred organisations. Part of the rationale for developing this standard was the recognition that human well-being is an important measure to complement the traditional measures of output. The standard, ISO 27500, is not an operational standard but highlights the principles, values, and beliefs that make organisations human centred. The standard draws on a wealth of ergonomic and human factor design principles that are known to be successful across a range of organisational structures from large to small private or public organisations. Seven principles were identified that characterise a human- centred organisation that encompass individual perspectives, usability of products and systems, and social responsibility that includes being trustworthy. Through efforts based on a systems approach encompassing human factors these principles are known to make significant contributions to overall productivity. Engaging a Diverse Multi-National, and Multi-Cultural Workforce We suggest at least two of these principles have high relevance to the complex, multidimensional, and fast- paced world of the biopharmaceutical sector that operates across multiple organisational and cultural boundaries. Attention to the principles of ensuring individual differences is an organisational strength and valuing employees to create a meaningful work environment will have positive impact in a multicultural environment. Create a Meaningful Work Environment that Values Employees – the Engaged Workforce It is important to remember that people deliver on organisational objectives Strategy Comparing 2003 to 2015, the global industry has grown 41per cent in terms of revenue, 53 per cent in terms of R&D spend with a 100 per cent increase in clinical projects.
21w w w . p h a r m a f o c u s a s i a . c o m and utilise their skills and capabilities to adapt to a variety of situations. Not surprisingly, therefore, there is evidence that indicators of worker wellbeing are linked to performance. Meaningful work supports not only our wellbeing but also our engagement and absorption into the work that we do. These are essential ingredients for releasing the creativity of research and development scientists to bring new products into the market. Innovation in both developing new products and processes requires individuals who are engaged and confident within their roles. Innovation is hampered by stress and distraction, particularly by the distraction of leadership when it is inconsistent, irresponsible, excluding, silent, and by the distraction of conflict or lack of connection and understanding between individuals. It is supported by tuning into the bigger picture the benefits to those who use our products; in other words, each seeing the value of their contribution and how their work makes a difference. Within the healthcare industry, our ultimate endgame is to improve human health through whatever aspect our work may involve. However, it is perhaps too simplistic to assume these links drive a meaningful work place. For front-line medical Staff there is a risk of compassion fatigue and burnout often related to workplace stress. A human-centred approach would suggest that the balance needs to be struck between financial rewards and the meaning the work brings to the individual in terms of their own sense of being and what matters most to them. Creating the right blend of performance measures that are linked to the ultimate patient value will provide transparency in decision making. Organisations make work meaningful by: Identifying the meaning• Expressing the meaning• Living by the meaning (all efforts • aligned to it) Repeating it often• Strategy Disengaged Engaged Productivity Leader Leadership Effectiveness Team Team Effectiveness The Lens of Culture The Lens of Culture The Lens of Culture Figure 1 The impact of engagement and dis-engagement on Leader and Team Behaviour. Awareness of multicultural dimensions is key
22 Pharma Focus Asia ISSUE - 29 2017 Strategy Human factors also indicate that people work best when they are valued and feel included in the workplace. This has an important aspect in the biopharmaceutical world of the 21st Century. With so many enterprises working across wide cultural and organisational boundaries, the industry is one of collaboration and partnerships. To get the best from these collaborative networks, the individuals need to feel valued, that they have a voice and are invited to use it, and that they contribute to meaningful goals. Failure to satisfy these basic human factors creates a risk that the performance of the teams becomes transactional, adhering to the status quo and focussed on intermediate goals. Figure1 outlines the influence of engagement and disengagement of leaders and their staff on their own and their team’s performance. Supportive leaders develop human centred and holistic approaches that significantly modify team behaviours. Measures of Engagement The difficult aspect of working with people across the multidimensional matrices involved in biopharmaceuti- cal innovation include how to meas- ure the engagement of individuals, and how their experience of work relates to how they feel. A variety of methods are present to measure work engagement, and are all self-reported measures. Engagement is an experi- ential state, an experience that is very personal to the individual involved and covers many aspects of thoughts, feelings and autonomy. Individuals are engaged when they experience their work as being part of something with colleagues they trust. The converse of engagement relates to high levels of work place stress and an absence of absorption in work. Dis-engagement can limit performance of leaders and impact their teams. Leaders need to be trusted and engender trust between their colleagues. Much research has been undertaken in this area but some early work provides some simple rules that openness / congruity in actions of leaders, having shared values and understanding the limits of decision making with feedback provide a guide that appears relevant to the complex multi-organisational and cultural biopharma ecosystem. Individual Differences are an Organisational Strength A recommended Human-Centred principle is to see individual differences as an organisational strength. There are no ‘standard persons’. An ergonomic approach takes into consideration the whole, allowing multiple viewpoints and create environments that support a range of body types and social networks.
23w w w . p h a r m a f o c u s a s i a . c o m WE CARE & CONNECT YOUR PHARMA
24 Pharma Focus Asia ISSUE - 29 2017 AuthorBIO Andrew A Parsons PhD has worked in Biopharma in a variety of Senior Executive and Non-Executive Roles. Initially trained in Pharmacology and Neuroscience he worked in External Innovation to maximise performance across organisational and cultural boundaries. He is an accredited coach and has interests in systems design. Sue Cruse has extensive experience as a leader and as a coach, working at senior levels across a range of sectors and organisations. She has led building energy, resilience and resourcefulness, across an employee population, to support sustainable high performance. An accredited Executive Coach with an MSc in Behavioural Change. This is perhaps even more important in the multi-cultural and global nature of business today. Push and Pull Approaches to Ensure Human-Centred Leadership Many industries have embraced ergo- nomic approaches to ensure critical performance. This is especially so in the case of high hazard industries such as the nuclear and aviation industries. Within these areas, a focus on safety is also a key property of the sector. Perhaps it is time to learn from professional ergonomists / human factor professionals in creating systems that enable performance across the complexity of the biopharma indus- try? As the industry continues to frag- ment and disperse, the tacit knowledge that resides in the experience of skilled professionals is likely to be lost. Drug discovery is a socio-technical enterprise that crosses the boundaries of hard experimental data and a huge range of uncertainties regarding prediction of ultimate clinical safety and efficacy and value. This system has some similari- ties with other high technology indus- tries that span the divide between hard empirical observations and the human perspective. A recent development in engineering systems to allow appropriate control of safety aspects in these socio- technical enterprises has been proposed. Approaches such as these may well provide the appropriate risk manage- ment infrastructure—the pull—to ensure appropriate performance. In this context, we suggest push approaches are based on building individual skills and an infrastructure to create feedback and learning. Challenges of mental health issues related to work place stress are becoming apparent in many cultures. Whereas a engaged workplace facilitates performance, prolonged periods of stress can have significant negative effects. Salutogeneis is a concept devel- oped by Aaron Antonovsky that focuses on an individual’s ability and resources to promote health rather than on treat- ment or managing risks. This approach is widely used in public health and seems appropriate in the workplace setting. The key elements of a salutogenic approach are the ability to develop and utilise general resources of wellbeing and maintain a problem solving orienta- tion through a sense of coherence and meaning. Developing general resources across a multicultural workforce requires a focus on the individual. Building on psychosocial approaches provides an individual framework to work cohesively within the community. Several areas of individual skill modelling are appro- priate within the salutogenic approach to build engagement and include the five factors of wellbeing, building mindfulness skills and being in flow are part of being actively and attentive. A recent model also highlights indi- vidual skills to enable presence with self and others as a leader. Push programmes to enable engage- ment across multicultural boundaries should focus on the following areas to maximise value to the individual and organisation Mindfulness/paying attention• Managing emotions• Building self-awareness of values,• beliefs, and meaning Solution focus• Conclusions A focus on how people interact with their work is an established scientific discipline that has been widely used in other safety-critical industries. The international standards organisation has developed a series of principles to support orientation of work activities at a board level to ensure that companies develop appropriate working practices to maximise their performance. We suggest that in the fast paced, multicultural, and dispersed biopharma industry today these principles are critical to the success of the socio-technical endeavour of Pharmaceutical R&D. All these principles are important and we suggest an initial starting point would be to focus on the level of employee engagement across the system to ensure adherence to principles relating to diversity and meaning in the workplace. The opportunities presented in the biopharmaceutical business sector can provide significant value to everyone involved — from investors to customers. Adopting a push and pull approach to what is done is essential to maximise performance. A human- Centred experiential learning process to develop leaders, managers, and employees is also an essential prerequisite for success. Paying attention to the ‘human’ will enable solutions to be developed for the essential leadership challenges mentioned above. References are available at www.pharmafocusasia.com Strategy
MEDIA PARTNERS AN INITIATIVE BY SUPPORTED BY For more information or to register, contact us at +971 4 361 9616 info@pharmamanufacturingmena.com or visit www.pharmamanufacturingmena.com • Meet with key local, regional, and international pharmaceuticals manufacturers • Learn about the latest technologies used in pharma manufacturing • Hear from leaders and key decision makers about strategic visions and initiatives for the industry • Understand the level of collaboration between the different stakeholders to advance the pharma market in the region • Gain insights about the latest global technical and operational trends • Network with your peers from the industry • Get CME credits and boost your career Key Benefits of Attending Some Key Speakers Exclusive 10% Discount for PharmaFocusAsia subscribers. Please use the code MPM17PFA to avail the discount. Bahaa Aboud, National Operation Manager, Tamer Group, KSA Dr. Bassam M. Alwon, Director, Establishments Inspection Department, Drug Sector, Saudi Food & Drug Authority SFDA, KSA Faisal Dail, General Manager, AJA Pharmaceutical IndustriesCo. KSA Mohamed Al Rifai, Quality Operations Senior Manager, Pfizer, KSA Salah Alkowaiter, Director of Quality and Compliance, SPIMACO, KSA Suleiman Aldajeh, Head of Research & Development, SAJA Pharmaceuticals, KSA Andrew East, Production and Engineering Director, ARABIO, KSA Wasif Azeem, Director Quality Operations, Jamjoom Pharma
26 Pharma Focus Asia ISSUE - 29 2017 Innovations in patient recruitment coupled with thoughtful local implementation are a step forward in our relentless pursuit to simplify the patient journey. David Yoshii, Senior Director Global Site Solutions PAREXEL International Patient Recruitment in Asia Reducing the clinical burden Clinical TriAls
27w w w . p h a r m a f o c u s a s i a . c o m Clinical TriAls T oday, there are many innovative, new approaches to patient recruitment and the number continues to grow. The driver behind these innovations is the challenge that many western countries face in recruiting patients for participation in clinical studies. The concept of patient recruitment is quite simple. It involves recruiting the right patients, at the right time, and in the right numbers. However, we encounter hurdles in applying a ‘one size fits all’ approach for these innovations, and to ensure successful enrolment, the recruitment tactics should consider local needs and challenges. number of clinical sites is expected to rapidly increase within the next few years. For the coming wave of new sites in China, strong partnerships/ collaborations with investigators and sites that enable them to deliver will be a key factor for success. In Japan, the challenges are different, and more similar to western countries. There is more competition for a limited patient pool and the population is shrinking. Frustration with the limitations to the current approaches is creating a market that is more and more open to new ideas. Data- driven feasibility is just beginning to gain acceptance and patient- centric approaches are also attracting attention. Such an environment requires innovative approaches and strategies, which are tailored to these markets. Keys to Innovation Innovations can come in the form of products and process improvements. Global innovation coupled with thoughtful local implementation is essential to succeed. To accomplish this, one needs to hire and develop the right talent, and work with the right partners, to foster innovations, develop them, and subsequently implement them in the best possible way. Local implementation of patient recruitment innovation requires knowledge of not only the challenges, but also the needs of the specific markets. Proof Point: National Cancer Centre Singapore (NCCS) In 2016, BMC Women’s Health published a study1 titled “Barriers and facilitators for clinical trial participation among diverse Asian patients with breast cancer: a qualitative study.” The study was conducted in the NCCS, which treats 75 per cent of cancer patients in Singapore and has a yearly outpatient 1 https://bmcwomenshealth.biomedcentral.com/ articles/10.1186/s12905-016-0319-1 Challenges for Different Geographies In Asia, there are challenges unique to the region for clinical trial recruitment, compared to the western world. For example, in China with a population of 1.4 billion people, the shortage is not in patients, but in site staff capable and experienced at delivering quality clinical trial results. On October 8 this year, the China Food and Drug Agency (CFDA) announced a new site certification process. Hospitals are now able to self-register as a clinical trial site, with the responsibility for qualifying such sites lying with the study sponsors. As a result, the
28 Pharma Focus Asia ISSUE - 29 2017 attendance of more than 130,000. In this study, various focus groups studied females over the age of 21 with breast cancer, who were able to provide informed consent and attend the focus group by themselves. The study examined the factors that influence patient recruitment into clinical trials in Asia, each factor showcasing an area of clinical trial recruitment with the potential to lessen the patient burden and improve the overall experience. These were found to include: 1. Knowledge and Attitude: Several patients in the study said they had not heard of the term “clinical trial,” and many that had heard of the term were previously or currently enrolled in one. This lack of familiarity would be a potential hurdle for recruiters, because patients would be less likely to seek out clinical trials if they had no concept of their existence. However, it turned out that 80 per cent of the participants asked for more information about clinical trials, showing that there is a desire for information, but inadequate means to obtain it. 2. Reasons to Join: This study highlighted the individual, medical and societal factors affecting the patient’s decision to participate in clinical trials. One deciding factor for some of the women in the study was how the study was introduced to them. The women preferred and were more trusting of studies that were introduced to them by their doctors–highlighting the need for clinical trials to work with local institutions and within the local Asian community to target potential patients. 3. Relaying the Information: Another important take away from the study is that many participants said simpler language and visual aids, such as recordings and pictures should be used to relay the ICFs (Informed Consent Forms) and other information regarding clinical trials – including promotion of other clinical trials. Recruiters need to simplify the information and tailor it to audiences to make it easier for the patient to understand. Clinical TriAls
29w w w . p h a r m a f o c u s a s i a . c o m AuthorBIO DavidYoshiiistheSeniorDirectorforGlobalSiteSolutions,covering feasibility, patient recruitment, site alliances, and other site related strategies for clients at PAREXEL International. His career spans over 20 years in drug development in various global leadership roles. He joined PAREXEL in 2011. Needs of Specific Markets: Getting the Word Out The study conducted by BMC Women’s Health shows there is an opportunity to improve how we approach clinical trials. The industry is rapidly embracing patient centric methodologies, as a means to improve the patient experience, with the potential to improve recruitment rates, increase compliance with study procedures and reduce withdrawals. Increasingly technologies such as “web listening” are being employed to more accurately analyse the sentiment of patients and caregivers, as well as identify key influencers related to a specific indication. For Asia, this requires adapting technology for local languages, as well as differences in social media preferences. This approach allows companies to fine tune their approaches to provide valuable information about the disease, therapies, as well as the availability of clinical trials. Needs of Specific Markets: The Clinical Site Investigator sites are critical to the success of any clinical trial. PAREXEL alone has value-driven partnerships with hundreds of clinical sites across the world, of which one in four sites are located in Asia, to support drug development for our clients’ investigational medicinal products. These sites, located in Japan, China, Korea, Taiwan, and in key countries throughout the rest of Asia, provide a means for patients to not only access innovative, new therapies, but have an improved clinical trial experience. Creating these partnerships in Asia is especially important for trial participation and diversity, as shown by the FDA in the 2015-2016 Global Participation in Clinical Trials Report where the majority of Asian trial participants in global studies were at non-US sites. Identifying the right sites isn’t easy. Data-driven feasibility is an approach to support site selection. Unfortunately, it is highly dependent on the robustness of the data being employed. For some countries, historical data is sometimes scarce, depending on the indication or drug’s mechanism of action. This entails augmentation, which requires tailoring the approach to what is optimal in the specific country. In Japan and China, collaborating with Site Management Organisations (SMOs) that provide study nurse dispatch services to clinical sites has proven effective, in addition to other country-specific approaches. Needs of Specific Markets: Relaying the Information Patient recruitment doesn’t end with identifying the patient, but requires the patient to consent to participate in the clinical trial. For the patient to give consent, they must first have a comprehensive understanding of the study. Some tools on the market try to make this information easily digestible with the use of animation to provide the patient with an overview of the study and related information – these tools are being actively used in China, Taiwan, Korea, and Japan. Such tools are often tailored culturally with voice overs in the local language and with animation that not only appeals to young children, but also adults and elderly patients, due to the ease of comprehension. There have already been increased trial consent rates, improved compliance /retention and shortened recruitment timelines in the studies where these tools have been implemented. An important factor is ensuring that the animation is culture agnostic and therefore acceptable in these very particular markets, and the simplicity of implementation is important to meet the needs of highly variable site environments. Reflections Approaches for patient recruitment must have one thing in common: they must make things simpler for the patient. Participating in a clinical trial is filled with anxiety and uncertainties, especially coupled with existing challenges from the underlying disease. Reducing the anxiety and clinical trial burden are obvious steps to make things simpler for the patient. The industry has decades and decades of experience in running clinical trials. However, as treatments continue to evolve, there is a need to advance the way we run the clinical trials, to not only provide evidence of efficacy and safety, but to also gain further insights into how we can provide additional value for patients and investigator sites. Innovations in patient recruitment coupled with thoughtful local implementation are a step forward in our relentless pursuit to simplify the patient journey. Local implementation of patient recruitment innovation requires knowledge of not only the challenges, but also the needs of the specific markets. Clinical TriAls
30 Pharma Focus Asia ISSUE - 29 2017 Clinical Trails
31w w w . p h a r m a f o c u s a s i a . c o m Landmark global XANTUS real-world programme showed low rates of stroke and major bleeding of 0.9 per cent and 1.7 per cent per year respectively with rivaroxaban, generally consistent with Phase III Rocket AF trial. John Battersby, Medical Writer, Bridges Publishing Pte Ltd Low Rates of Stroke and Major Bleeding with Rivaroxaban Confirmed by Global Study XANTUS pooled results study R esults of the pooled analysis of the global XANTUS real- world study programme were announced recently at the European Society of Cardiology (ESC) Congress in Barcelona, Spain.The study investigated the use of the non-vitamin K antagonist oral anticoagulant (NOAC) rivaroxaban for stroke prevention in patients with non-valvular Atrial Fibrillation (AF) (irregular heart beat). The study showed low rates of both stroke and major bleeding, including fatal intracranial (skull) bleeds in AF patients on Xarelto® for stroke prevention. The majority (96.1 per cent) of the pooled XANTUS population did not experience stroke / systemic embolism, major bleeding and all-cause death. This is generally consistent with the Phase III ROCKET AF trial and reaffirms the safety and efficacy of rivaroxaban in AF management. The global XANTUS programme is the largest prospective observational study on a single NOAC for stroke prevention in AF. This pooled analysis combined real-world data from three prospective, single-arm, multi-centre studies across multiple regions, which together followed more than 11,000 patients from 47 countries: 1. XANTUS, the largest of the studies, which followed 6,784 patients from Canada, Israel and 10 countries across Europe. Clinical TriAls
32 Pharma Focus Asia ISSUE - 29 2017 2. XANAP, the first Pan-Asian real- world study of rivaroxaban in AF stroke prevention, which followed 2,273 patients from 10 countries / territories in Asia (Hong Kong SAR, Indonesia, South Korea, Malaysia, Philippines, Singapore, Taiwan, Thailand, Vietnam and Pakistan). 3. XANTUS-EL which involved 2,101 patients from 17 countries in Eastern Europe, Middle East, Africa, and Latin America. Unmet Needs in Atrial Fibrillation (AF) AF is a heart condition characterised by irregular heartbeats which increases the risk of stroke caused by blood clots by five-fold. Strokes due to AF are also more severe, causing disability in over 50 per cent of patients and generally worse outcomes than strokes due to other causes. The incidence of AF increases with age. The prevalence of AF is a global issue with the number of AF patients growing rapidly and expected to have doubled by 2050. AF is especially of concern in Asia due the regions rapidly ageing populations. It is estimated that by 2050, Asia will have 72 million AF patients, and 2.9 million among them will suffer from an AF-associated stroke. The good news is AF-related strokes can be prevented. However, there is still a significant number of AF patients in Asia not receiving optimal anticoagulant therapy for stroke prevention. Older anticoagulant therapy with Vitamin K Antagonist (VKAs) such as warfarin makes effective anticoagulation harder for patients and physicians due to its manifold food and drug interactions, regular blood monitoring requirements and risk of intracranial (skull) bleeding. These serious disadvantages cause VKAs to be under-used or under-dosed in AF stroke prevention, leaving patients unprotected. “NOACs like rivaroxaban can potentially address this medical challenge as they are at least as effective as traditional warfarin therapy in preventing strokes in AF patients, but are easier to administer and carry a significantly lower risk of the life- threatening intracranial bleeding,” said Professor John Camm, the Professor of Clinical Cardiology at St George’s University of London who presented the results at ESC. “While this has been well proven in clinical trials and real-world studies, the consistency of the combined data from the worldwide XANTUS programme adds significantly to our understanding on the safety of NOACs in AF patients, and gives physicians the confidence to prescribe rivaroxaban in daily clinical practice.” The Studies In the XANTUS pooled analysis, a total of 11,121 patients were enrolled into the three real-world studies and included in the analysis. Patients were from 47 countries in Western Europe / Canada/ Israel (47.5 per cent), Eastern Europe (23.2 per cent), East Asia (20.1per cent), the Middle East/Africa (6.2 per cent) and Latin America (3.0 per cent). The major- ity of patients (73.1per cent) initially received rivaroxaban 20mg once daily, while 25.1 per cent, 1.6 per cent and 0.2 per cent of patients received rivaroxaban 15mg once daily, 10mg once daily and other doses, respectively. There were differences in patient demographics, Clinical TriAls
33w w w . p h a r m a f o c u s a s i a . c o m clinical characteristics as well as stroke and bleeding risks among the study regions. Patients with higher CHADS2 (stroke risk) or CHA2DS2-VASc (bleed- ing risk) scores at baseline were more likely to experience major bleeding, stroke /systemic embolism or death. Results from XANTUS pooled population showed low rates of both stroke and major bleeding with rivar- oxaban at 0.9 per cent and 1.7per cent per year respectively, generally consist- ent with those in the ROCKET AF trial. Mean CHADS2 (stroke risk) and CHA2DS2-VASc (bleeding risk) scores for the pooled population were 2.0 and 3.5 respectively. The findings were generally consistent across different regions and patient populations worldwide based on each of the individual studies. In XANAP, the Asian arm of XANTUS programme, the rates of both stroke and major bleeding were low at 1.7 per cent and 1.5 per cent respectively, generally consistent with Phase III ROCKET AF East Asia study and two other studies in the programme. CHADS2 (stroke risk) and CHA2DS2-VASc (bleeding risk) scores in XANAP were 2.3 and 3.7 respectively, higher than the mean scores of the XANTUS pooled population The majority (96.6 per cent) of patients on rivaroxaban in the study did not experience stroke / systemic embolism, major bleeding, and all-cause death. About XANTUS Pooled Analysis This is a pre-planned pooled analysis of the prospective, observational XANTUS, XANAP and XANTUS-EL studies of unselected patients with AF newly starting rivaroxaban for stroke prevention. Patients were followed for 1 year, at ~3-month intervals, or for ≥30 days after permanent discontinuation. Primary outcomes were major bleeding, Adverse Events (AEs) or Serious AEs (SAEs) and all-cause mortality. Secondary outcomes included symptomatic thromboembolic events and non-major bleeding. Treatment-emergent major outcomes were adjudicated by a central committee. 11,121 patients were included (Western Europe/Canada/ Israel: 47.5per cent; Eastern Europe: 23.2 per cent; East Asia: 20.1 per cent; Middle East and Africa: 6.2per cent; and Latin America: 3per cent). Of the patients 73.1per cent received rivaroxaban 20mg once daily (od) and 25.1per cent rivaroxaban 15mg (od); 72.4per cent had prior anticoagulation therapy. Mean age was 70.5 years and mean weight was 80.0kg.Co-morbidities included congestive heart failure (21.2per cent), hypertension (76.2per cent), diabetes mellitus (22.3per cent), prior stroke/non-central nervous system (CNS) systemic embolism (SE)/transient ischaemic attack (TIA; 21.3per cent) and prior myocardial infarction (MI; 8.9per cent). Rates of treatment-emergent major outcomes were: major bleeding 1.7 (1.5–2.0); all-cause mortality 1.9 (1.6–2.2); stroke/non-CNS SE 1.0 (0.8–1.2); stroke 0.9 (0.7–1.1). About XANAP XANAPis the first Pan-Asian, prospective, single-arm, observational study of 2,273 patients designed by Bayer to evaluate the safety and effectiveness of rivaroxaban for stroke prevention with non-valvular AF from 435 sites across Asia (Hong Kong SAR, Indonesia, South Korea, Malaysia, Philippines, The global XANTUS programme is the largest prospective observational study on a single NOAC for stroke prevention in AF. Clinical TriAls
34 Pharma Focus Asia ISSUE - 29 2017 AuthorBIO John has been science and technical writer for many years and has focused on medical and healthcare issues for more than a decade. He has spent the last 20 years in South East Asia, mainly based in Singapore, working as a freelance journalist and media adviser to the pharmaceutical industry. Singapore, Taiwan, Thailand, Vietnam and Pakistan) in routine clinical practice. All treatment and dosing decisions were at the discretion of the treating physicians and patients were followed up for one year or until 30 days after premature discontinuation. Bleeding events and major thromboembolic events were centrally adjudicated by an independent committee. At the end of the study, the majority (96.6 per cent) of patients on rivaroxaban did not experience stroke / systemic embolism, treatment- emergent major bleeding, and all-cause death. Overall, patients experienced treatment-emergent major bleeding at a rate of 1.5 per 100 patient-years (1.5 per cent per year); most of these major bleeds were treated using standard clinical measures. Rates of fatal bleeding were 0.2 per 100 patient-years 0.2 per cent per year). Critical organ bleeding occurred at a rate of 0.8 per 100 patient-years (0.8 per cent per year), which included intracranial bleeding at a rate of 0.7 per 100 patient-years (0.7 per cent per year). Stroke occurred at a rate of 1.7 per 100 patient-years (1.7per cent per year). The analyses from this study provide valuable insights on the usage of rivaroxaban by patients in Asia for non-valvular AF stroke prevention. “Strokes in AF patients are highly preventable. These robust findings further support rivaroxaban as a therapy of choice for stroke prevention in AF patients, with a low rate of major bleeding,” said Dr Foo Chuan Kit, Head of Medical Affairs of Bayer Pharmaceuticals Division for Asia- Pacific. “By involving Asian patients in this worldwide programme, we offer valuable insights to help physicians in the region safely and effectively lower the risk of stroke in their AF patients.” Latest ESC Guidelines NOACs are recommended as first-line anticoagulants in the prevention of AF-associated stroke in the latest international guidelines for the management of AF by the European Society of Cardiology (ESC). It is stated that NOACs offer better efficacy, safety and convenience compared with VKAs. NOACs are broadly preferable to VKAs in the vast majority of patients with AF. About Rivaroxaban Rivaroxaban is the world’s most widely prescribed NOAC that has been prescribed to 31 million patients worldwide and more than 3 million patients in Asia-Pacific for the management of blood clots in seven distinct indications, including stroke prevention in AF. Rivaroxaban is also the most broadly indicated NOAC, approved for seven indications, protecting patients across more venous and arterial thromboembolic conditions than any other NOAC: 1.The prevention of stroke and systemic embolism in adult patients with non-valvular AF with one or more risk factors 2.The treatment of Deep Vein Thrombosis (DVT) in adults 3.The treatment of Pulmonary Embolism (PE) in adults 4.The prevention of recurrent DVT and PE in adults 5.The prevention of Venous Thromboembolism (VTE) in adult patients under going elective hip replacement surgery 6. The prevention of VTE in adult patients undergoing elective knee replacement surgery 7. The prevention of atherothrombotic events (cardiovascular death, myocardial infarction or stroke) after an Acute Coronary Syndrome (ACS) in adult patients with elevated cardiac biomarkers and no prior stroke or transient ischaemic attack when co-administered with acetylsalicylic acid (ASA) alone or with ASA plusclopidogrel or ticlopidine. While regulatory approvals may differ from country to country, across all indications, rivaroxaban is approved in more than 130 countries. References are available at www. pharmafocusasia.com XANAP is the first Pan-Asian, prospective, single-arm, observational study of 2,273 patients designed by Bayer to evaluate the safety and effectiveness of rivaroxaban for stroke prevention with non-valvular AF from 435 sites across Asia. Clinical TriAls
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36 Pharma Focus Asia ISSUE - 29 2017 W ith the demand for wearables and sensors in clinical trials on the rise, pharmaceutical companies are increasingly faced with the challenges of both rising costs and market saturation of similar drugs – and that is where Clinical Research Organisations (CROs) come into play. From both a technology perspective and a processes perspective, CROs can leverage remote medical devices, unleashing an opportunity to collect novel endpoints and supplemental data that may improve the regulatory case. This also opens the door for CROs to make the case for reimbursement more As real world evidence becomes an integral part for many clinical trials, wearables allow for monitoring and data collection anywhere the patient is located – freeing researchers of the location barrier of real world evidence. Xavier Flinois, President, PAREXEL Informatics Wearables in Clinical Trials Where we are & where we are going Clinical TriAls
37w w w . p h a r m a f o c u s a s i a . c o m compelling, open up trial participation to a wider population and/or reduce site visits for patients who may not live close to an investigative site. Although medical devices like spirometers and activity monitors have been used in clinical trials for almost a decade, modern wearable technology is improving the patient experience and lessening the data management burden. Outdated spirometers or activity monitors had to be transported back to the clinical site, where the data was then transcribed into an Electronic Data Capture (EDC) system, and downloaded – a process prone to transcription and human errors. Now wearables are more scalable and allow clinical sites to digitally collect the information without transporting or transcribing. These updates improve both trial efficiency and data accuracy. Regulating Medical Devices The use of medical devices for study endpoints has yet to receive regulatory guidance, but at a Drug Information Association Meeting in December 2016, the Federal Drug Administration (FDA) expressed cautious optimism that these devices could provide better and more timely insight into a patient’s health status. FDA speakers went so far as to say that researchers need not necessarily use medical devices with a 510(k) approval or CE stamp; consumer grade devices can be used as long as they are ‘fit for purpose.’ As regulators and drug companies accept the use of wearables, medical devices will play a more prominent role in clinical trial data collection, particularly in Phase II and III trials. Wearables by Phase: Phase I With the initial influx of information gathering in Phase I, wearables fit well into the protocol of the early clinical stage. One instance of this was a trial that added remote sensors into Phase I. The objective of adding this technology was to both pilot the new sensors as well as to compare the sensor data to the in-clinic data for a diabetes trial. With successful collaboration, the trial facilitators were able to produce a trial design that minimised the impact on the core protocol while maximising the number of devices. In all, six remote medical devices were added to the study –spirometer, blood pressure, pulse oximeter, blood glucose monitor, weight scale and activity monitor. Site and subject acceptance was high. It is expected that Sponsors developing new biologics where the benefit is best measured by sensors and/or where sensors provide valuable health status information to subjects, will begin piloting the applicable sensors in Phase I in parallel to their first in human clinical trials. Wearables by Phase: Phase II-III Because of the lack of regulatory guidance, the validated use of specific mobile health devices to deliver primary endpoint data is expected over the next 12–24 months. In Phase II and III trials, clinical trial sponsors will likely use medical devices as exploratory endpoints to mature their understanding of the utility of sensor- based endpoints. For some disorders, medical devices will be used across all phases as combination products. According to the FDA, “Combination products are therapeutic and diagnostic products that combine drugs, devices, and/or biological products. FDA expects to receive large numbers of combination products for review as technological advances continue to merge product types and blur the historical lines of separation between FDA’s medical product centers, which are made up of the Center for Biologics Evaluation and Research (CBER), the Center for Drug Evaluation and Research (CDER), and the Center for Devices and Radiological Health (CDRH).”11 Wearables by Phase: Phase IV The growing demand for wearables in clinical trials is also being seen in Phase IV studies. The post-marketing demands and remote connectivity make wearables an ideal Phase IV component. Sponsors have the opportunity to make a strong case to regulators, especially in regard to why certain drugs should move to an over-the-counter status since the general population has the ability to use commonly available medical devices to either self-diagnose or monitor a particular health condition. Thanks to the maturation of this technology medical devices can now securely and wirelessly transfer data, increasing the integrity of clinical trial data. For example, once a reading is taken on a blood pressure monitor, that data is automatically downloaded to a hub (a device plugged into an electrical outlet). The patient then plugs in the hub once and takes his or her readings on the prescribed schedule. All of the data transfer is handled seamlessly and securely without the need for manual intervention – reducing the chance of human error. If the patient forgets to plug in the hub, the data is stored on the medical device until it’s plugged in. Alternatively, there is an option to securely transfer data via a companion app on a smartphone. What Else can Wearables Enable? Medical devices offer a multitude of possibilities for researchers that go 1 “About Combination Products” - https://www.fda.gov/ CombinationProducts/AboutCombinationProducts Effective medical device use requires best-in-class medical, HEOR, biostatistics, logistics, technology and clinical trial conduct capabilities. Clinical TriAls
38 Pharma Focus Asia ISSUE - 29 2017 far beyond collecting blood pressure. Using the data collected from wearables, predictive analytics may allow medical devices to alert researchers of future medical events. The application of predictive analytics to connected medical device data may enable the identification of subjects who are who are not protocol compliant such that the sites can intervene to increase subject retention. A predictive analytics for sensor-based data will enable increased patient retention and safety. Wearables not only simplify data collection and improve patient safety; this technology allows for the advancement of international partnerships where multiple teams can be connected in real-time. Remote and in-clinic data can be “fused” together for sites and study teams to view side-by-side in Phase I-IV clinical trials. This takes away the barrier of geographic location for multiple sites working across the globe, and allowing this increased comparison of diverse data will increase the integrity of the results on an international scale. The value of wearables is not limited to trials sites. As Real World Evidence (RWE) becomes an integral part for many clinical trials, wearables allow for monitoring and data collection anywhere the patient is located – freeing researchers of the location barrier of RWE Wearables have created a structure where data collection is aboundary-free factor in clinical trial management. End-to-End Medical Device Components It is critical that Sponsors leverage a medical device solution that securely and wirelessly transmits the data with the ability to store, visualise and alert from the big data time series data; however, the application of medical devices is not just a technology exercise. The performance of medical devices must be evaluated prior to use for study endpoints to understand if the device generates data within acceptable parameters and in comparison to the manufacturer's claims. Informed Consent Forms must be adapted for the collection of personal data and there are data storage and data transmission/re-use implications, particularly in the European Union. There are health economic and outcomes research considerations that must be taken into account to ensure that the associated endpoints are fit for purpose for regulatory submissions. Logistics also plays an important role on the front end, when devices are acquired, kitted and distributed to sites in a timely manner that accommodates the storage limitation at the sites. At the end of a trial, the devices need to be returned; cleansed or destroyed; and all data deleted from the device. Effective medical device use requires best-in-class medical, HEOR, biostatistics, logistics, technology and clinical trial conduct capabilities. Where does this Go Next? So where can wearables take the industry? The shrinking size of medical devices and connected implantable device along with evolving technology will further enable the collection of novel and complementary data to support regulatory submissions and reimbursement. With experience and regulatory acceptance, the potential for connected medical devices is extraordinary. These devices have the potential to change the way clinical trials are conducted; to broaden participation in clinical trials at a time when subject recruitment is major barrier; to enable virtual trials; and to reduce clinical trial costs. The challenge today is not deciding on whether to use a mobile health device, but the effective integration into drug development programmes. AuthorBIO Xavier Flinois leads PAREXEL’s Informatics division, which provides innovative technology solutions to help optimise patient engagement, clinical and regulatory processes. He brings to PAREXEL more than 25 years of experience in technology and healthcare, including senior leadership positions with global companies in the clinical software, consulting and IT services areas. Clinical TriAls
39w w w . p h a r m a f o c u s a s i a . c o m
40 Pharma Focus Asia ISSUE - 29 2017 Technology transfer is not just limited to industries and R&D. A research scientist working in R&D may also work with universities. There are several examples of patent or product commercialisation happening in universities. This article focuses on how technology transfer can be coupled with knowledge translation. Vivek Dave, Sachdev Yadav, Harshavardhan ML Yadav, Isha Mehta Department of Pharmacy, Banasthali University Merging Technology Transfer with Knowledge Translation Academic to industrial research T he government and research academics are increasingly aware of the relevance of their result to the industrial sector. The term knowledge translation was coined to represent proactive strategies to communicate research findings to those in a position to put the findings into practice. As it happens in most cases, the first consideration is given to market size. Simply put, it means that the market where we are supposed to market the product should be large enough to trade it in a very big volume. Moreover, it is very important to see weather Research & Development
41w w w . p h a r m a f o c u s a s i a . c o m the intended result can be patentable or not, especially in the pharmaceutical industries. Technology transfer does not always involve a patentable invention, but also the transfer of the intact technology including copyrights, proficiency, and others. A good patent is that which cannot be overcome by any other universities; a weak patent will allow other universities or researchers to come up with good amendments on our idea leading to the problems of licensing. Some universities require employees and graduate students to report all inventions to the universities and, upon request, execute a formal assignment document. The Bayh Dole Act, a nonprofit organisational research and its documentation work that is closely concerned to the field, permits funding agencies to grant inventors requests to retain title, provided the universities have waived election of the title. However, if universities believe an invention is valuable, they will usually elect title, apply for patents, and then license the rights exclusively back to the inventors. This is the procedure usually followed in the case of inventors who obtain venture capital to form companies to develop their discoveries. However, a number of universities support their employees who wish to preserve the title to their inventions, and have sensible plans to ensure growth. Most universities also assert ownership over non patentable materials created by their employees and recorded information generated by their employees. The quality of industry technology transfers is based on the student and industry relationships. The interaction with industry can also educate faculty and students with regard to salaries and working conditions in industry. Students learn that scientists in industry also publish. They learn that scientists in industry can spend less time raising funds for their labs than those in academia. It also has the potential for educating them with regard to the rewards of working in industry. This interaction can go a long way towards ridding industry of the stigma that has caused it recruitment problems in the past. Technology transfer can also provide funds for students and resources for enhancing programmes. They set some goals for preparing and distributing technology transfer guidelines which are shown in figure 1. The Bayh Dole Act Providing the Platform for Universities Technology Transfer The Bayh Dole Act enacted on December 12, 1980 (The Patent & Trademark Act Amendments) (Public Law 96-517) created a uniform patent policy among federal agencies that fund research. Bayh-Dole enables small businesses and non-profit organisations, including universities, to retain title to materials and products they invent under federal funding. Subsequent amendments created uniform licensing guidelines and expanded the law to include all federally funded contractors (Public Law 98-620). The implementing regulations for Bayh-Dole are published at 37 CFR Part 401. Regulations Implementing Federal Patent and Licensing Policy Regarding ‘Rights to Inventions Made by Nonprofit Organisations, Universities and Small Business Firms’ are Codified at 37 Cfr Part 401. The Following Summarises the Significant Aspects of these Regulations • The provisions apply to all inventions conceived or first actually reduced to practice in the performance of a federal grant, contract, or cooperative agreement. This is true even if the federal government is not the sole source of funding for either the conception or the reduction to practice. The provisions do not, however, apply to federal grants that are primarily for the training of students and postdoctoral scientists • The university has an obligation to disclose each new invention to the federal funding agency within two months after the inventor discloses it in writing to the universities • The decision whether or not to retain title to the invention must be made within two years after disclosing the invention to the agency. This time may be shortened, if, due to publication of research results or public use, the one-year US statutory patent bar has been set in motion. Under such circumstances, the universities must make an election at least sixty days before the end of the statutory period. If the university does not elect to retain title, the agency may take title to the invention • Upon election of title, the universities must file a patent application within one year, or prior to the end of any Research & Development Figure 1 Goals for preparing and distributing technology transfer guidelines Defining Rights And Responsibilities Goals Revneu for the creator students Assisting students in commercialising their products Making inventions available tp all consumers
Human-Centred Design in Biopharma: Need of the hour
Human-Centred Design in Biopharma: Need of the hour
Human-Centred Design in Biopharma: Need of the hour
Human-Centred Design in Biopharma: Need of the hour
Human-Centred Design in Biopharma: Need of the hour
Human-Centred Design in Biopharma: Need of the hour
Human-Centred Design in Biopharma: Need of the hour
Human-Centred Design in Biopharma: Need of the hour
Human-Centred Design in Biopharma: Need of the hour
Human-Centred Design in Biopharma: Need of the hour
Human-Centred Design in Biopharma: Need of the hour
Human-Centred Design in Biopharma: Need of the hour
Human-Centred Design in Biopharma: Need of the hour
Human-Centred Design in Biopharma: Need of the hour
Human-Centred Design in Biopharma: Need of the hour
Human-Centred Design in Biopharma: Need of the hour
Human-Centred Design in Biopharma: Need of the hour
Human-Centred Design in Biopharma: Need of the hour
Human-Centred Design in Biopharma: Need of the hour
Human-Centred Design in Biopharma: Need of the hour
Human-Centred Design in Biopharma: Need of the hour
Human-Centred Design in Biopharma: Need of the hour
Human-Centred Design in Biopharma: Need of the hour
Human-Centred Design in Biopharma: Need of the hour
Human-Centred Design in Biopharma: Need of the hour

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Human-Centred Design in Biopharma: Need of the hour

  • 1. Issue 29 2017 www.pharmafocusasia.com Wearables in Clinical Trials Where we are & where we are going Patient Recruitment in Asia Reducing the clinical burden
  • 2. kromasil@akzonobel.com India & Middle-East: +91 22 2778 7338 Worldwide: +46 31 58 70 00 www.kromasil.com For the purification of • Peptides • Small proteins • Oligonucleotides • Small molecules HPLC columns and bulk media for analysis and API purification by industrial-scale chromatography High performance spherical silica
  • 3. Foreword Prasanthi Sadhu Editor market. Design thinking enables organisations to bring-in cross-departmental innovation, deliver value-added solutions and unleash market opportunities. HCD brings together company leadership both strategic and operational, stakeholders that work in a collaborative environment with uniform goals and unified approach to solutions. This process includes defining roles and responsibilities for all those involved. By integrating human-centred research, the molecular development process benefts from parallel human-centred research throughout the discovery and development phase. This also helps in increasing the productivity by choosing the most useful potential medicines among many alternatives and help articulate real value to users for a given medicine. By supporting human-centred research, R&D organisations can signifcantly augment their tools for guiding personalised medicine and create robust portfolios of products that users strongly value. In the cover story of this issue, authors Andrew Parsonsand Susan Cruse suggest that a human-centred experiential learning process to develop leaders, managers, and employees is quintessential for success. Paying attention to the ‘human’ will enable development of solutions for addressing leadership challenges. If we hope to create something of lasting value, we need to start with what people want — not just with what’s technically possible! IDEO, a global design firm. Innovation and technology advancements play a key role in product design and development, but it is imperative that companies bring in a human-centred approach. The advent of new technologies such as virtual reality, augmented reality, digital assistant etc. throws light on integrating those into human lives for better application and experience. Think of a Fit-bit – it tracks one’s physical activity, sleep and throws inputs on areas of improvement thus helping an individual stay physically active. Human Centred- Design (HCD) is a methodology that focuses on the people that you serve and places them at the center of design and implementation. HCD combines research and insights with business and technology requirements to produce the best output. It is indeed more relevant for the life sciences and healthcare sectors as the onus is on producing effective drugs and care. From the pharma industry perspective, design thinking could be using design to come up with ideas to effective connect with and offer care to patient. A study conducted by the Drug Information Association (DIA) in collaboration with the Tufts Center for the Study of Drug Development (CSDD) indicates more than 65 per cent of pharma and biotech companies are inclined to invest in drug development through patient centric initiatives. As the demand for patient-centred drug development and service continues to rise, a human centred approach could be the differentiator for companies in the Human-Centred Design in Biopharma Need of the hour
  • 4. 2 Pharma Focus Asia ISSUE - 29 2017 Contents Strategy 06 Future Prospects of Biotherapeutics and Challenges Ambikanandan Misra, Faculty of Pharmacy The Maharaja Sayajirao University of Baroda Clinical Trials 26 Patient Recruitment in Asia Reducing the clinical burden David Yoshii, Senior Director, Global Site Solutions PAREXEL International 30 Low Rates of Stroke and Major Bleeding with Rivaroxaban Confirmed by Global Study XANTUS pooled results study John Battersby, Medical Writer, Bridges Publishing Pte Ltd 36 Wearables in Clinical Trials Where we are & where we are going Xavier Flinois, President, PAREXEL Informatics Research & Development 40 Merging Technology Transfer with Knowledge Translation Academic to industrial research Vivek Dave, Sachdev Yadav, Harshavardhan ML Yadav Isha Mehta Department of Pharmacy, Banasthali University 48 Creating the Perfect Capsule Choosing the right shell excipient for your formulation challenges Bjorn Vergauwen, Principal Scientist, Rousselot Manufacturing 52 The Rise in Sterile Manufacturing A focus on containment Christian Dunne, Global Product Manager ChargePoint Technology Information Technology 58 Take a Pass on the 3pm Samples Steve Madden, Software Product Manager Mass Spectrometry Agilent Technologies 62 Books The Human-Centred Biopharma Organisation Andrew A Parsons, Reciprocal Minds Limited Susan M Cruse, Leadership Mastery Limited COVERSTORY 18 48 30
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  • 6. 4 Pharma Focus Asia ISSUE - 29 2017 Editor Prasanthi Sadhu Editorial Team Debi Jones Grace Jones Art Director M Abdul Hannan Product Manager Jeff Kenney Senior Product Associates David Nelson Peter Thomas Sussane Vincent Product Associates Austin Paul Ben Johnson Veronica Wilson Circulation Team Naveen M Nash Jones Sam Smith Subscriptions In-charge Vijay Kumar Gaddam Head-Operations S V Nageswara Rao AdvisoryBoard Frank Jaeger Regional Sales Manager, Metabolics, AbbVie, USA Douglas Meyer Senior Director, Aptuit Informatics Inc., USA Christopher-Paul Milne Director of Research, Tufts Center for the Study of Drug Development, Tufts University, USA Alan S Louie Research Director, Health Industry Insights an IDC Company, USA Georg C Terstappen Director and Head of Biology, Neuroscience Discovery AbbVie Deutschland GmbH und Co. KG, Germany Sanjoy Ray Director, Strategic Alliances & Health Innovation Merck, US Rustom Mody Senior Vice President and R&D Head Lupin Ltd., (Biotech Division), India Phil Kaminsky Chair, Department of Industrial Engineering and Operations Research University of California, Berkeley, USA Neil J Campbell President & CEO, Helomics Corporation HealthCare Royalty Partners University of Liverpool, UK Laurence Flint Head Clinical Research Cough, Cold & Respiratory Disease Novartis Consumer Health, Inc., USA Kenneth I Kaitin Director and Professor of Medicine, Tufts Center for the Study of Drug Development, Tufts University, USA Ochre Media Private Limited Media Resource Centre,#9-1-129/1,201, 2nd Floor, Oxford Plaza, S.D Road, Secunderabad - 500003, Telangana, INDIA, Phone: +91 40 4961 4567, Fax: +91 40 4961 4555 Email: info@ochre-media.com Pharma Focus Asia is published by © Ochre Media Private Limited. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, elec- tronic, photocopying or otherwise, without prior permission of the publisher and copyright owner. Whilst every effort has been made to ensure the accuracy of the information in this publication, the publisher accepts no responsibility for errors or omissions. The products and services advertised are not endorsed by or connected with the publisher or its associates. The editorial opinions expressed in this publication are those of individual authors and not necessarily those of the publisher or of its associates. Copies of Pharma Focus Asia can be purchased at the indicated cover prices. For bulk order reprints minimum order required is 500 copies, POA. www.pharmafocusasia.com | www.ochre-media.com A member of Confederation of Indian Industry In Association with Strategy
  • 7. It takes a unique blend of expertise to deliver the right results From clinical development to commercial production At Vetter, we look at your product from every angle. And help you find answers that make a difference in efficiency, productivity, safety, quality, and growth. From initial process design through high-speed fill and finish, learn how a partnership with Vetter will keep your product moving smoothly towards success. More than 35 years of experience in aseptic filling Expertise with many compound classes, including biologics Highly trained experts in key technical areas Integrated life cycle management Innovative drug delivery options State-of-the-art cGMP manufacturing Excellent global regulatory support Vetter Development Service Vetter Commercial Manufacturing Vetter Packaging Solutions US inquiries: infoUS@vetter-pharma.com • Asia Pacific inquiries: infoAsiaPacific@vetter-pharma.com • Japan inquiries: infoJapan@vetter-pharma.com • EU and other international inquiries: info@vetter-pharma.com Answers that work www.vetter-pharma.com
  • 8. 6 Pharma Focus Asia ISSUE - 29 2017 Advancements in the biotechnology have presented pharmaceutical manufacturing industries biotherapeutics which are promising as potential future therapeutics. Diverse categories of biotherapeutics are coming into the market which range from monoclonal antibodies, growth hormones and cytokines to vaccines. Present topic will cover the future prospects and challenges to the biotherapeutics. Ambikanandan Misra, Faculty of Pharmacy, The Maharaja Sayajirao University of Baroda B iotherapeutics or biological products are generally produced using living cells or organisms (recombinant DNA technology, controlled gene expression and antibody technologies). It may be manufactured using biotechnology derived from natural sources or produced synthetically. Recombinant hormones, vaccines, monoclonal antibody based products, growth factors, blood products and advanced technology products (gene and cell therapy biological products) are few of the biotherapeutics. According to definition of the PHS (Public health service) act of USFDA, biological products are defined as a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesised polypeptide), or analogous product which are applicable to the prevention, treatment, or cure of a disease or condition of human beings. Proteins Future Prospects of Biotherapeutics and Challenges Strategy
  • 9. 7w w w . p h a r m a f o c u s a s i a . c o m Strategy Gene screening & vector insertation Host cell expression & cell culture Protein production and purification Formulation & Development and Analysis Storage & handling are classified as drugs as well as biologics in USFDA but proteins are regulated as a biological product, except any chemically synthesised polypeptide, under the BPCI act. Difference between Biologics, Biosimilars and Generics The generic version of biolog- ics are known as biosimilars in Europe, Similar biologics in India, follow-on Pharmaceutical in USA and Japan, subsequent entry biologics in Canada, and biocomparables in Mexico. The origin of the terminology lies
  • 10. 8 Pharma Focus Asia ISSUE - 29 2017 Parameters Characterisation technique Primary sequence (peptide map andamino acid sequence analysis), immunogenicity (immunoassay) other identity indicators IE, HPLC, gel electrophoresis Potency Cell-based bioassay, gene expression bioassay, ADCC, CDC Conformation Near/far UV circular dichroism spectroscopy, Fourier transform infrared spectroscopy, X ray crystallography and differential scanning calorimetry Glycosylation onosaccharide composition analysis, oligosaccharide profile, CE, LC-MS, MS/MS, ESI, MALDI-TOF Phosphorylation Peptide mapping with MS Truncation SE-HPLC, gel electrophoresis, AUC, peptide mapping with MS, RP HPLC Glycation Peptide mapping with (MS, HPLC), methylation, isomerisation (RP HPLC) Pegylation HPLC, CE Aggregation SE-HPLC, gel electrophoresis, Light scattering and AUC Oxidation Peptide mapping with MS Deamidation Capillary IEF, peptide mapping with MS, and CEX-HPLC, C-terminal lysine (capillary IEF, peptide mapping with MS, and CEX-HPLC), misfolds (RP-HPLC) Host cell proteins ELISA, DNA, endotoxin (Limulus amoebocyte lysate assay) Binding Cell assays, spectroscopy, ELISA Biological activity Cell assays, animal models Abbreviations: IE, ion exchange; HPLC, high performance liquid chromatography; ADCC, antibody-dependent cell-mediated cytotoxicity; CDC, complement-dependent cytotoxicity; CE, capillary electrophoresis; LC–MS, liquid chromatography–mass spectroscopy; MS/MS, tandem mass spectrometry; ESI, electrospray ionisation; MALDI-TOF, matrix-assisted laser desorption/ionisation time of flight MS; AUC, analytical ultracentrifugation; CEX, cation exchange; IEF, isoelectric focusing; SE, size exclusion; RP-HPLC, reverse phase HPLC; ELISA, enzyme-linked immunosorbent assay; QSE, quality safety and efficacy. in the loss of patent protection of first generation innovator biologics in last decades. Biologics are at least 1000 times larger than conventional drugs or generic drugs in size containing hundreds of amino acids joined by peptide bonds to form a polypeptide. It is very difficult to establish reproducibility for biosimilars whereas reproducibil- ity can be easily achieved by generics or small molecules conventional drugs. Biologics, biosimilars and generics are needed to exhibit comparabil- ity, biosimilarity, and bioequivalence respectively. The non-medical switch- ing is not allowed in biologics and biosimilars whereas it is allowed in generics. Biopharmaceutical produc- tions methods are more complex than chemical production methods so production cost automatically goes higher than generic counter- parts. Although the goals are same — to treat the disease—biotherapeutics and generics differ substantially in ways that might affect innovation, safety, costs, clinical adoption, patient access, and pricing. Manufacturing of Biotherapeutics The stable Biotherapeutics consist of Primary (amino acid sequence) and Secondary structures (α-helix and β-sheets) which are folded to form 3D-Tertritary structures that is converted into quaternary structure. The biological activity can be attributed to glycosylation and sialylation. The characterisation remains the challenge for biotherapeutics due to larger size and structural complexity. A typical biotherapeutics production involves following steps: The methods of biotherapeutics characterisation are divided into quality, safety and efficacy of product which requires clearance by regulatory body and further comparability exercise. There is a significant improvement in formulation of biotherapeutics and characterisation of the products due to recent guidelines on the International Conference on Harmonisation Q8 Strategy
  • 11. 9w w w . p h a r m a f o c u s a s i a . c o m on pharmaceutical development and the roll-out of the Quality by Design and Process Analytical Technology, comparability of biotechnological / biological Products subject to changes in their Manufacturing process Q5E and quality of biotechnological products: stability testing of biotechnological / biological products Q5C. There are methods for characterisation of biotherapeutics as mentioned in the table. Switching and Interchangeability in Biosimilars Reference product biologics and their biosimilars are very important treatment options for multiple diseases and have the potential to expand the possibilities for our patients. Switching studies evaluate all the parameters change with exposure to interchangeable product with reference one. The main purpose of this study is to demonstrate the risk in terms of safety or diminished biological activity between interchangeable molecules. As per FDA a product is interchangeable with biosimilars, if the manufacturer proves that it is expected to produce same clinical result in same patient only is product considered as safe. Comparability studies are performed between a biosimilars and its reference product, but studies between one biosimilars and another are not done; two separate biosimilars may have been compared to the same reference but not between themselves. Challenges in Development of Biosimilars European Medicine Agency (EMEA) has first issued guidelines defining biosimilar approval pathway which has been adopted and/modified by several countries. Guidelines issued by WHO are almost similar to EMEA guidelines. However, similarities in the guidelines is just the tip of the iceberg, and there is an intense need for streamlining the standards. Furthermore, companies are suspending the development of biosimilars at clinical stages, hesitating to conduct single and global development programmes due to the changes in the IP rights, evolving guidelines (many countries are changing their guidelines abruptly as the understanding and definitions of biosimilarity, interchangeability, substitution etc. evolve), unknown patient-to-patient variability between the biosimilar and reference biologic in Phase I/II studies, large variability encountered in PK/PD studies, safety, efficacy and immunogenicity profiles due to manufacturing quality, uncertainty in Phase III trials (whether to consider the Phase III trials as non-inferiority trials or bioequivalence trials) etc. Many countries require that the reference biologic be approved /licensed/ marketed in the country. So, it becomes very difficult for the companies to target other countries using same biosimilar, as it would raise the questions due to large number of quality comparisons to be established, number of different toxicology and clinical studies to be performed. High development costs force companies to focus first on developed nations with large market size which will delay/limit development of biosimilars Strategy 2008 No guidelines• on bio similar in the U.S. Debate on key• issues Pathway• passed as part of the ACA 2010 2009 Implementation• of the Biologics Price Competition and Innovation Act 2012 Draft guidence• issued from U.S. FDA with Clarity on• biosimilar approval pathway 2014 Purple Book• published Sandoz and• Celltrion field biosimilar candidate applications for regulatory approval 97 biosimilars• in development 2013 $42B• Total global sale Current trends in biosimilars
  • 12. 10 Pharma Focus Asia ISSUE - 29 2017 Strategy AuthorBIO Ambikanandan Misra is Professor of Pharmacy at Faculty of Pharmacy at The Maharaja Sayajirao University of Baroda. He has been associated with the field of pharmaceutical sciences for more than 38 years. 42 PhD and 128 Master students have completed their dissertation under his guidance. He has 7 books, 40 book chapters and 156 peer reviewed publications in reputed journals. He has filed 29 national and international patents out of which 8 have been granted so far. Source of RWD United States European States Approval Procedure Approval is based on the information indicative of the biological product is highly similar along with no meaningful discrepancy in their safety, potency and / or the purity to that of the reference biological product (1) Approval is based on by comparing the biosimilar product with its reference biological product demonstrate that there are no significant changes between them (Applicable clinical data necessary to compare with the inventor) (2) Naming Manufacturer and FDA determines the naming of biosimilar product (3) Approving body of the individual member states determines to name of the biosimilar product (3) Labeling A statement has to be written on the product that it is a biosimilar for specified indication(s) as well as administration route(s), and if biosimilar is interchangeable with reference biological product (1) A clear indication on all the biosimilar products with the black symbol and standardised descriptive statement (4) Interchangeability FDA determines the interchangeability of the biosimilar product to the reference biologic based on the optional evaluation (5) EMA declines interchangeability of the biosimilar product to the reference biologic (6) Automatic Switching Executed by state laws (7) Executed by individual member states (6) Pharmacovigilance Endorsements Regulation and the awareness of the product specific post- marketing safety monitoring by FDA (1) Product name and Batch number are the identities of all biologics (4) Regulatory frameworks in biosimilars in EU & USA medicines. The cumulative market potential may reach beyond EUR 100 billion in next five years. There are at least 50 distinct biosimilars in pipeline and will be delivered successfully in next five years. Biosimilars can bring improvements to patient outcomes by providing more treatment options to physicians and reducing the need for rationing. Conclusion Though adopted and evolved from similar background, a large amount of discrepancies exists between regulatory guidelines being followed in different countries. There is a mandate for harmonising the guidelines at global level which will ease the biosimilars product manufacturing in several countries enabling the companies to globally market their biosimilar products. There is a potential opportunity for biopharmaceutical companies for low-cost manufacturing in semi- regulated and non-regulated markets. Companies need to review and follow all quality, safety, and efficacy parameters of different countries and revising the development plan for biosimilars from time to time addressing the country-by country differences. India is gearing up with the companies that are adopting guidelines more in line with EU and USA. Soon, more Indian companies will get through the rigid approval framework including refined requirements of non-clinical and clinical evaluations; India is going to make its stance as a provider of low-cost biosimilar products. for countries with smaller markets. All of this mandates that the biosimilar guidelines evolve and be streamlined as soon as possible. Until then, there is no option other than to consider the specified pathways of each country. Streamlining will surely take time; but once done, there will be a step-wise approach for biosimilar authorisation /marketing in several countries. Thorough and defined quality characterisation tests, non-clinical studies, extent of clinical studies and standards for reference biologics will be specified which will help extrapolation of data from one indication to other approved indications of innovator product. It will also resolve the differences in nomenclature that may cause multiple revisions of clinical trials and marketing authorisation applications for consistency with guidelines and regulations. The Potential of Biosimilars A number of key biologics are going off patent by 2020, thus there is a huge potential for Biosimilar version of these
  • 14. 12 Pharma Focus Asia ISSUE - 29 201712 Pharma Focus AsiA ISSUE - 29 2017 How Best to introduce Medical Devices Class II Products into the Chinese Market How best to introduce medical devices class II products into the chinese market? Many Pharma companies are still bothering from China regulations. Having a partner who understands the opportunity and competitive environment of the Chinese marketplace is absolutely essential and can be the difference between success and failure. Phillips-Medisize explains the work to bring a rapid development of a variable dose pen injector in China through regulatory approval. Bill Welch, CTO, Phillips-Medisize Finding the most appropriate foreign manufacturing partners for Chinese companies in the medical devices marketplace involves complex studies and background research for suitable partnership candidate companies into a number of key issues. Foreign drug companies needtounderstandthismarket’schallengestocapitalize on the opportunities and obvious long-term benefits for both parties. By gaining an in-depth knowledge into the country’s regulatory body, an organization can leverage this experience to both advance its product and to create a solid and sustainable foundation for an expanding manufacturing strategy in China. With a sales volume of $ 48.5 billion in 2015 China is one of the world’s largest and fastest growing medical device markets. This represented a Compound
  • 15. 13w w w . p h a r m a f o c u s a s i a . c o m 13w w w . p h a r m a f o c u s a s i a . c o m Annual Growth Rate (CAGR) of some 22.3 percent between 2010 and 2015. Today, China is the world’s 2nd largest medical device market with overall healthcare expected to reach $ 1.3 trillion by the end of 2018. This market is expected to continue to grow strongly, with pharmaceutical expenditure expected to increase at a rate of almost 70 percent over the next five years.Finding the most appropriate reliable long- term global partners is an essential part in securing ongoing sustainable growth in that sector to satisfy demand. Currently, approx. 300 million Chinese patients are suffering from chronic diseases alone; this number is boundtoriseovertime.Suchdiseasesincludediabetes and many other conditions requiring treatment with medical devices for diagnostics and drug delivery. And this is just the home market – not taking product exports into consideration. Only the most advances high-tech organizations with a global presence producing innovative medical devices can offer the multi-faceted requirements in such a complex market place. The principal criteria include: 1. Speed of innovation , passage time to market – critical assets assessment to reach market viability 2. From Part to Market 3. Product Approval and Registration–knowledge and experience in and speedy execution of As a contract manufacturing organization (CMO) and a contract development and manufacturing organization (CDMO), Phillips-Medisize is one such forward-lookingcompanysatisfyingthecriticalfactors relevant for the vast Chinese markets in the Medical Devices Class II sector. More than just a molder, the company specializes in design through distribution services and has created an environment focused on high quality and adherence to rigorous time-to- market schedules. Furthermore, the company has had a design manufacturing center near Shanghai for the past three years. A newly added medical devices registration operation has been given to the medical device production facility that has Good Manufacturing Practice (GMP) from the China Food and Drug Administration (CFDA). This means that the paths – innovation and part to market – have already been cleared to a great extent. Phillips-Medisize already has in-depth insight into the many regulations, guidelines, protocols, procedures and codes of practice for Medical Devices Class II products and their timely implementations are the cornerstone of a long-lasting productive partnership. Last, but not least, the ability to recognize the unique market trends within China are part of the company’s strength. This gives this organization a vitally important competitive edge. In addition, familiarity with product testing and the final product registration are an important part of what Phillips-Medisize can offer potential partners in China. When it comes to Medical Devices Class II products, the Phillips-Medisize variable auto-dose pen injector, insulin pen, is a prime example of the classification. 1. Speed of Innovation The time between initial concept of the product or product development must be kept to an absolute minimum and without compromising fundamental part of the process. Here, the knowledge of all vital segments of state-of-the-art technology is, at the very best, a routine part of any appropriate company’s remit. Suitable partners must possess the critical assets essential to satisfy Chinese manufacturers. Commercial viability and market maturity are familiar phrases to any suitable candidate. Criteria include global presence, in-depth market knowledge in the guest country, fully trained design, development and implementation personnel able to work with its customers to deliver advanced automated assembly and quality control technologies on a long-term basis, which reduce manufacturing cost while, in tandem, improve quality. 2. From Part to Market Serving such a large, fast growing market such as China, and allowing for potentially prolonged approval times requires that device producers keep the time to market readiness for new products to an absolute minimum without compromising the process. Advertorial
  • 16. 14 Pharma Focus Asia ISSUE - 29 201714 Pharma Focus AsiA ISSUE - 29 2017 Insteadofaconventional‘linear’productdevelopment life cycle with manufacturing development and manufacturing stages after a large part of the product development phases has been completed, Phillips-Medisize has considerably shortened lead times to market by bringing forward two manufacturing stages to start and run parallel with the product proof of concept stage of development. Thus the concept development stage has become a concept and manufacturing development stage and the validation stage includes both product development and manufacturing elements. By adopting a systems engineering approach at an early proof-of-concept stage, the company also aims at reducing financial and other risks in efficient device development to meet more advanced technical requirements, as well as ensuring that required devices reach the market within agreed schedules. This is achieved by paying particular attention to each individual component contained within the drug delivery systems, as well as to the method by which the components, sub-systems and complete systems are fully integrated and work effectively with each other. The systems engineering approach is more robust than with linear product development, as it requires some engineers dedicated to systems and others to sub-systems development. For example, Phillips-Medisize states that although this involves higher up-front early development stage costs than with linear product development, it saves other expenses later on, e.g. if the need arises to trace back the cause for a device not properly functioning at a later stage in development or marketing. The potential higher up-front development costs are minimized by integrating Design for Manufacture (DFM) and Design for Assembly (DFA), as 80 percent of product cost and quality are often determined during the first 20 percent of the product development cycle. Manufacturing strategy must be fully aligned with device strategy in order to avoid end stage changes which may compromise stakeholder requirements or program feasibility. 3. Product Approval and Registration Bill Welch, Chief Technology Officer at Phillips-Medisize, explains the registration and approval process: Any serious contender, contract development and manufacturing organizations (CDMO), keen to enter the Chinese medical devices market, must be totally familiar with the time-consuming regulatory approval procedure. Again, taking the insulin pen as an example, the initial step to be taken is the appointment and retention of a qualified agent based in China who will coordinate registration with the CFDA, also known as the State Food and Drug Administration (SFDA) or simply State Drug Administration (SDA).
  • 17. 15w w w . p h a r m a f o c u s a s i a . c o m 15w w w . p h a r m a f o c u s a s i a . c o m This approach applies in a formal review process for the single device, the device and the drugs it delivers or in parallel reviews for the device and drug. Products should be treated both as the sum of the constituent drug and delivery device parts, but also as a complete treatment system. All the different routes along the registration and approval path influence the time to market speed. They are equivalent to speed control bumps along a motorway impeding rapid progress to a successful conclusion. Documents submitted in approval applications should include not only data on product performance, but also on, for example, risk analysis and technical requirements, animal trials, biocompatibility, bio safety, drug expiry and package as well as software aspects. The review process takes into account whether the device is produced in China, requiring a Device Manufacturing Permit (DMP), or imported from abroad, either in part or as a whole. Domestic Chinese and international approval status is taken into account, as well as whether production takes place as a certified GMP process and, in the case of a drug, whether it already has an import license. Authorization is granted if already approved in the producer’s home country. It is less complex to introduce new products into the Chinese market if they are produced in China, specifically or mainly for the Chinese market. Failing that, products should, at least, be either clinically trialed in their country of origin or supported by data showing that a medical device is ‘substantially equivalent’ to those already produced in and, therefore, approved in China. The local agent submits the device at a medical device evaluation center for approved by the CFDA and at provincial FDA locations, as both these bodies are responsible for regulations and guidance. They may well request additional clinical trials if new first of its-kind devices are submitted. Producers should have a well-developed clinical strategy and have backing of, for instance, risk- benefit analyses by an ethics committee in the EU or an equivalent Institutional Review Board (IRB) in the USA, which formally approves, monitors and reviews biomedical and research involving humans. The registration partner can encounter challenges during the approval process, such as substantial regulatory changes or newly introduced registration and certification requirements. It is therefore diligent to conduct gap analysis, to compare actual and desired performance, as a basis for timely corrective action. Information should be submitted in an easily understandable form and available in the appropriate local Chinese language at all levels. CFDA nationally and FDA at both provincial and city levels are involved with quality system inspection and post-market surveillance, the FDA city level for manufacturing site licensing. The entire process can be challenging as FDA officials are known to be inundated with drug and delivery device applications over past years. The CFDA receives over 10,000 new drug applications each year, but is limited by its review capacity of 5,000 to 6,000 pa. This has resulted in a backlog, estimated currently at around 21,000 submissions. The result is that foreign companies face potentially longer waiting times for approval than Chinese companies. In addition, approval times for new products can take longer than renewal approvals for existing products, some 20 percent or so longer for Class III devices and between 15-25 percent for new drugs and biologics (genetically-modified proteins derived from living entities). Advertorial Longer and more costly registration times may also be expected due to medical device classification in China according to CFDA’s SDA Order Number 15 differing significantly from EU and US classifications. For example, a Class II device in the USA or a Class IIa/IIb device in the EU could be considered Class III in China.
  • 18. 16 Pharma Focus Asia ISSUE - 29 201716 Pharma Focus AsiA ISSUE - 29 2017 FDA offices are not only suffering from staff shortages thus increasing work load for officials, they are also required to cope with the decentralized regulatory structure, absence of a common IT infrastructure and a lack of consistent policies which hinder effective communication between the various FDA offices. There is also limited ability to track national and global databases for adverse events, unlike tracking procedures that have become well established in the EU and North America. Apart from CFDA and FDA offices, establishment of contacts and a local interface with the Centre for Medical Device Evaluation (CMDE), the Centre for Drug Evaluation (CDE) and the General Administration of Quality Supervision, Inspection, and Quarantine (AQSIQ) are also advisable. This pressure on the regulatory and approval system is a development mainly as a result of the size and speed of growth of the Chinese healthcare market. Variable Dosing Prospects Medical device research consultancy Quality Invention (QI LLC) was involved with Phillips-Medisize in the insulin pen development. According to them, the consultancy’sprimegoalisthedesignanddevelopment of medical devices to address combination product challenges in the pharma industry. The consultancy is headed by Dr Min Wei, a registered patent agent, who not only holds a PhD in Material Science, but also MSc qualifications in Polymer and Computer Sciences, supplemented by a Master’s degree in Business Administration (MBA). Unlike variable-dose auto-injectors, Wei points out that fixed-dose auto-injectors do not address individual personalized medication needs for multiple doses, fail to meet different dosing needs of adults and children, present challenges to registration and compliance as combination products (combination of the drug and its delivery device), and are expensive if integrated into adaptive clinical trials. More usability data can be collected in clinical trials with variable-dose auto-injectors and they have greater dosing accuracy than conventional vial and syringe dosing. He states that variable-dose auto-injectors can be easily adopted for use with medicines that are already available in graduated pre-filled syringes, from e.g. Amgen, Genetech, Novartis and Sanofi, enabling a smooth transition into variable dosing for both patients and their doctors and other medical staff. According to Wei, the medicines so far available in this form and already administered in millions of units per year are Epoetin alfa (Epogen), Filgrastim (Neupogen), Enoxaparin sodium (Lovenox) and Methotrexate. But Relistor, Sumatriptan succinate, Invega, Stelara, Procrit and Humira are additional medicines calling
  • 19. 17w w w . p h a r m a f o c u s a s i a . c o m 17w w w . p h a r m a f o c u s a s i a . c o m A u t h o r BIO Bill Welch has over 25 years of contract design, development and manufacturing experience, primarily serving customers in the drug delivery, health technology and diagnostics markets. In his current capacity as Chief Technical Officer at Phillips-Medisize, he leads a global, over-600 person development, engineering, tooling, programme management and validation organisation. Bill has been with Phillips-Medisize since 2002. for variable dosing and which could also be efficiently dosed by a variable does injector. Wei adds that many more are in the pipeline. Due to greater fear of injections than adults, children (pediatric patients) have the greatest need for variable dosing, the quantity being determined by body weight or surface area. Bill Welch is of the opinion that there is evidence that adaptiveclinical trials (CTs), those where multiple formulations can be evaluated and where there is a prospect of modification later on in the trial. They are gaining in popularity, as they shorten study duration andreducecosts,improvechancesofsuccess,andare ethically superior. Most importantly, Welch maintains that variable-dose auto-injectors provide the flexibility to run adaptive CTs without design modifications or in excessive production quantities. He illustrates this with an example where a CT with a variable-dose auto-injector can reduce drug quantity needed by a factor of seven, compared to running the CT with fixed dosing, resulting in estimated cost savings of $12 million, based on seven doses per week over 52 weeks, with 400 patients, and assuming a $100 preparation cost for each CT drug unit. He refers to data in a report by K. Spenceret and others in the Journal of Diabetes Science & Technology; issue 6:1296, 2012. Typical Auto-Injector Design A typical variable-dose auto-injector is a graduated pre-filled syringe, which can be seen by the user via a viewing window in the pen housing. The user rotates a dialing cap on the top of the pen, so that it moves along a dosing scale marked on the pen body for the correct dose required. The user then removes the bottom cap and needle shield, removing the dialing cap to expose the actuation button, before placing the bottom of the injector against the area to be injected. Pressing the actuation button then triggers auto-injection. When the pen is removed from the injected area the user is required to replace the needle shield, or sharps cover, for safety reasons. Welch points out that such pens can be designed as a platform that enables 1mL long or 2.25mL variable- dose auto-injectors to be easily transformed into fixed- dose disposable and fixed-dose reusable versions without complete redesign, as the housing and many other components are identical across the entire platform, also when, for instance, a fixed-dose auto- injector is supplied with a connectivity function. This means that different types of auto-injectors can be produced on one assembly line. By gaining in-depth knowledge of the country’s regulatory procedures, an organization can leverage this experience to both advance its product and to create a stable foundation for a global expansion strategy in China and beyond. This means that proven success in China serves as a valuable marketing tool and the experience and knowledge can be invaluable for medical device manufacturers when entering other countries across the globe. The Chinese medical device market was recently valued at $27.7 billion and is projected to grow to an estimated $50.8 billion in 2020. Given the growth in medical device sales and the predicted rise in population in China at a rapid pace, this is undoubtedly a market that medical device companies are keen to enter in order to take advantage of the obvious and exciting opportunities. Advertorial
  • 20. 18 Pharma Focus Asia ISSUE - 29 2017 The biopharmaceutical industry is in continual change. Increased competition and diversity in business models creates a leadership challenge of sustaining growth and performance. To address this challenge, we outline a focus on Human Centred Organisations, with Leaders creating meaningful and engaged work environments to maximise performance sustainably. Andrew A Parsons, Reciprocal Minds Limited Susan M Cruse, Leadership Mastery Limited COVERSTORY Strategy The Human-Centred Biopharma Organisation
  • 21. 19w w w . p h a r m a f o c u s a s i a . c o m Strategy T o maximise performance, it is time to put the human in the centre of the complex, multicultural and dispersed ecosystem of biopharma innovation. The Challenge of Sustainable Growth - The Current Scenario The pharmaceutical industry has changed dramatically over the past 10 years. Despite a range of merger and acquisitions within large companies, the industry has grown in the number of companies selling products within the market. Comparing 2003 to 2015, the global industry has grown 41per cent in terms of revenue, 53 per cent in terms of R&D spend with a 100 per cent increase in clinical projects. Organisationally, the dispersed nature of the sector supports increased number of deals resulting in merger and acquisitions or IPO. The industry is therefore becoming increasingly fragmented and competitive in terms of revenue and organisational autonomy. Against this backdrop of increased fragmentation, it is apparent that successful projects and products remain elusive. The cost of development and easy access to medicines is a persistent issue that regulatory agencies and industry professionals are increasingly aware. There is an inherent tension within the system between the high levels of failure, the costs involved in development and commercialisation and the needs of public and private healthcare providers. Big Pharma has consequently adapted its strategy with wider global networks of research and development across hubs and a focus on the emerging markets. The
  • 22. 20 Pharma Focus Asia ISSUE - 29 2017 dispersed and global nature of the business has resulted in reductions within the knowledge base of discrete organisations and a drive to collaborate and gain expertise and know how from collaborators. A recent academic review highlighted key areas of collaboration including sharing and learning at organisational and team levels, and access to infrastructure and management expertise with appropriate governance control points of projects. These macro level changes in the pharma sector are evidence of some dramatic changes in operational business models. The days of large fully integrated pharmaceutical companies with depth and breadth of R&D projects and finances appear long gone. No doubt the model will continue to develop further over the next 10 years. The Leadership Challenge At a more specific or micro level of leaders and managers within individual companies, these macro level changes create some difficult challenges. Some key issues include how to create impact in decision making when you may work virtually or remotely? How to ensure effective and efficient communications across cultural boundaries and how to create engaged and productive teams and collaborations? There are no simple answers to these questions. We often focus on how to better use technologies and information. However, there are other approaches commonly used to ensure the most productive interface between people and what they do. In this article, we aim to raise awareness of human factor approaches and outline some pull and push approaches to ensure people can operate at their best, especially in the fast paced, multicultural, and global biopharma industry of today. What are Human Factors? Human factors encompass a professional science often known as ergonomics. It relates to the understanding of interactions among humans and other elements of a system. Human factors research has been applied across high- hazard sectors to develop safe practices that not only anticipate, but also mitigate, human error. Within the U.K. NHS, the importance of human factors has been highlighted and identified as an avenue for collaboration between disciplines providing key benefits in the utilisation of people, their needs and containing costs. Human-Centred Organisations In 2016, some guiding principles were developed by the International Standards Organisation (ISO) for developing human centred organisations. Part of the rationale for developing this standard was the recognition that human well-being is an important measure to complement the traditional measures of output. The standard, ISO 27500, is not an operational standard but highlights the principles, values, and beliefs that make organisations human centred. The standard draws on a wealth of ergonomic and human factor design principles that are known to be successful across a range of organisational structures from large to small private or public organisations. Seven principles were identified that characterise a human- centred organisation that encompass individual perspectives, usability of products and systems, and social responsibility that includes being trustworthy. Through efforts based on a systems approach encompassing human factors these principles are known to make significant contributions to overall productivity. Engaging a Diverse Multi-National, and Multi-Cultural Workforce We suggest at least two of these principles have high relevance to the complex, multidimensional, and fast- paced world of the biopharmaceutical sector that operates across multiple organisational and cultural boundaries. Attention to the principles of ensuring individual differences is an organisational strength and valuing employees to create a meaningful work environment will have positive impact in a multicultural environment. Create a Meaningful Work Environment that Values Employees – the Engaged Workforce It is important to remember that people deliver on organisational objectives Strategy Comparing 2003 to 2015, the global industry has grown 41per cent in terms of revenue, 53 per cent in terms of R&D spend with a 100 per cent increase in clinical projects.
  • 23. 21w w w . p h a r m a f o c u s a s i a . c o m and utilise their skills and capabilities to adapt to a variety of situations. Not surprisingly, therefore, there is evidence that indicators of worker wellbeing are linked to performance. Meaningful work supports not only our wellbeing but also our engagement and absorption into the work that we do. These are essential ingredients for releasing the creativity of research and development scientists to bring new products into the market. Innovation in both developing new products and processes requires individuals who are engaged and confident within their roles. Innovation is hampered by stress and distraction, particularly by the distraction of leadership when it is inconsistent, irresponsible, excluding, silent, and by the distraction of conflict or lack of connection and understanding between individuals. It is supported by tuning into the bigger picture the benefits to those who use our products; in other words, each seeing the value of their contribution and how their work makes a difference. Within the healthcare industry, our ultimate endgame is to improve human health through whatever aspect our work may involve. However, it is perhaps too simplistic to assume these links drive a meaningful work place. For front-line medical Staff there is a risk of compassion fatigue and burnout often related to workplace stress. A human-centred approach would suggest that the balance needs to be struck between financial rewards and the meaning the work brings to the individual in terms of their own sense of being and what matters most to them. Creating the right blend of performance measures that are linked to the ultimate patient value will provide transparency in decision making. Organisations make work meaningful by: Identifying the meaning• Expressing the meaning• Living by the meaning (all efforts • aligned to it) Repeating it often• Strategy Disengaged Engaged Productivity Leader Leadership Effectiveness Team Team Effectiveness The Lens of Culture The Lens of Culture The Lens of Culture Figure 1 The impact of engagement and dis-engagement on Leader and Team Behaviour. Awareness of multicultural dimensions is key
  • 24. 22 Pharma Focus Asia ISSUE - 29 2017 Strategy Human factors also indicate that people work best when they are valued and feel included in the workplace. This has an important aspect in the biopharmaceutical world of the 21st Century. With so many enterprises working across wide cultural and organisational boundaries, the industry is one of collaboration and partnerships. To get the best from these collaborative networks, the individuals need to feel valued, that they have a voice and are invited to use it, and that they contribute to meaningful goals. Failure to satisfy these basic human factors creates a risk that the performance of the teams becomes transactional, adhering to the status quo and focussed on intermediate goals. Figure1 outlines the influence of engagement and disengagement of leaders and their staff on their own and their team’s performance. Supportive leaders develop human centred and holistic approaches that significantly modify team behaviours. Measures of Engagement The difficult aspect of working with people across the multidimensional matrices involved in biopharmaceuti- cal innovation include how to meas- ure the engagement of individuals, and how their experience of work relates to how they feel. A variety of methods are present to measure work engagement, and are all self-reported measures. Engagement is an experi- ential state, an experience that is very personal to the individual involved and covers many aspects of thoughts, feelings and autonomy. Individuals are engaged when they experience their work as being part of something with colleagues they trust. The converse of engagement relates to high levels of work place stress and an absence of absorption in work. Dis-engagement can limit performance of leaders and impact their teams. Leaders need to be trusted and engender trust between their colleagues. Much research has been undertaken in this area but some early work provides some simple rules that openness / congruity in actions of leaders, having shared values and understanding the limits of decision making with feedback provide a guide that appears relevant to the complex multi-organisational and cultural biopharma ecosystem. Individual Differences are an Organisational Strength A recommended Human-Centred principle is to see individual differences as an organisational strength. There are no ‘standard persons’. An ergonomic approach takes into consideration the whole, allowing multiple viewpoints and create environments that support a range of body types and social networks.
  • 25. 23w w w . p h a r m a f o c u s a s i a . c o m WE CARE & CONNECT YOUR PHARMA
  • 26. 24 Pharma Focus Asia ISSUE - 29 2017 AuthorBIO Andrew A Parsons PhD has worked in Biopharma in a variety of Senior Executive and Non-Executive Roles. Initially trained in Pharmacology and Neuroscience he worked in External Innovation to maximise performance across organisational and cultural boundaries. He is an accredited coach and has interests in systems design. Sue Cruse has extensive experience as a leader and as a coach, working at senior levels across a range of sectors and organisations. She has led building energy, resilience and resourcefulness, across an employee population, to support sustainable high performance. An accredited Executive Coach with an MSc in Behavioural Change. This is perhaps even more important in the multi-cultural and global nature of business today. Push and Pull Approaches to Ensure Human-Centred Leadership Many industries have embraced ergo- nomic approaches to ensure critical performance. This is especially so in the case of high hazard industries such as the nuclear and aviation industries. Within these areas, a focus on safety is also a key property of the sector. Perhaps it is time to learn from professional ergonomists / human factor professionals in creating systems that enable performance across the complexity of the biopharma indus- try? As the industry continues to frag- ment and disperse, the tacit knowledge that resides in the experience of skilled professionals is likely to be lost. Drug discovery is a socio-technical enterprise that crosses the boundaries of hard experimental data and a huge range of uncertainties regarding prediction of ultimate clinical safety and efficacy and value. This system has some similari- ties with other high technology indus- tries that span the divide between hard empirical observations and the human perspective. A recent development in engineering systems to allow appropriate control of safety aspects in these socio- technical enterprises has been proposed. Approaches such as these may well provide the appropriate risk manage- ment infrastructure—the pull—to ensure appropriate performance. In this context, we suggest push approaches are based on building individual skills and an infrastructure to create feedback and learning. Challenges of mental health issues related to work place stress are becoming apparent in many cultures. Whereas a engaged workplace facilitates performance, prolonged periods of stress can have significant negative effects. Salutogeneis is a concept devel- oped by Aaron Antonovsky that focuses on an individual’s ability and resources to promote health rather than on treat- ment or managing risks. This approach is widely used in public health and seems appropriate in the workplace setting. The key elements of a salutogenic approach are the ability to develop and utilise general resources of wellbeing and maintain a problem solving orienta- tion through a sense of coherence and meaning. Developing general resources across a multicultural workforce requires a focus on the individual. Building on psychosocial approaches provides an individual framework to work cohesively within the community. Several areas of individual skill modelling are appro- priate within the salutogenic approach to build engagement and include the five factors of wellbeing, building mindfulness skills and being in flow are part of being actively and attentive. A recent model also highlights indi- vidual skills to enable presence with self and others as a leader. Push programmes to enable engage- ment across multicultural boundaries should focus on the following areas to maximise value to the individual and organisation Mindfulness/paying attention• Managing emotions• Building self-awareness of values,• beliefs, and meaning Solution focus• Conclusions A focus on how people interact with their work is an established scientific discipline that has been widely used in other safety-critical industries. The international standards organisation has developed a series of principles to support orientation of work activities at a board level to ensure that companies develop appropriate working practices to maximise their performance. We suggest that in the fast paced, multicultural, and dispersed biopharma industry today these principles are critical to the success of the socio-technical endeavour of Pharmaceutical R&D. All these principles are important and we suggest an initial starting point would be to focus on the level of employee engagement across the system to ensure adherence to principles relating to diversity and meaning in the workplace. The opportunities presented in the biopharmaceutical business sector can provide significant value to everyone involved — from investors to customers. Adopting a push and pull approach to what is done is essential to maximise performance. A human- Centred experiential learning process to develop leaders, managers, and employees is also an essential prerequisite for success. Paying attention to the ‘human’ will enable solutions to be developed for the essential leadership challenges mentioned above. References are available at www.pharmafocusasia.com Strategy
  • 27. MEDIA PARTNERS AN INITIATIVE BY SUPPORTED BY For more information or to register, contact us at +971 4 361 9616 info@pharmamanufacturingmena.com or visit www.pharmamanufacturingmena.com • Meet with key local, regional, and international pharmaceuticals manufacturers • Learn about the latest technologies used in pharma manufacturing • Hear from leaders and key decision makers about strategic visions and initiatives for the industry • Understand the level of collaboration between the different stakeholders to advance the pharma market in the region • Gain insights about the latest global technical and operational trends • Network with your peers from the industry • Get CME credits and boost your career Key Benefits of Attending Some Key Speakers Exclusive 10% Discount for PharmaFocusAsia subscribers. Please use the code MPM17PFA to avail the discount. Bahaa Aboud, National Operation Manager, Tamer Group, KSA Dr. Bassam M. Alwon, Director, Establishments Inspection Department, Drug Sector, Saudi Food & Drug Authority SFDA, KSA Faisal Dail, General Manager, AJA Pharmaceutical IndustriesCo. KSA Mohamed Al Rifai, Quality Operations Senior Manager, Pfizer, KSA Salah Alkowaiter, Director of Quality and Compliance, SPIMACO, KSA Suleiman Aldajeh, Head of Research & Development, SAJA Pharmaceuticals, KSA Andrew East, Production and Engineering Director, ARABIO, KSA Wasif Azeem, Director Quality Operations, Jamjoom Pharma
  • 28. 26 Pharma Focus Asia ISSUE - 29 2017 Innovations in patient recruitment coupled with thoughtful local implementation are a step forward in our relentless pursuit to simplify the patient journey. David Yoshii, Senior Director Global Site Solutions PAREXEL International Patient Recruitment in Asia Reducing the clinical burden Clinical TriAls
  • 29. 27w w w . p h a r m a f o c u s a s i a . c o m Clinical TriAls T oday, there are many innovative, new approaches to patient recruitment and the number continues to grow. The driver behind these innovations is the challenge that many western countries face in recruiting patients for participation in clinical studies. The concept of patient recruitment is quite simple. It involves recruiting the right patients, at the right time, and in the right numbers. However, we encounter hurdles in applying a ‘one size fits all’ approach for these innovations, and to ensure successful enrolment, the recruitment tactics should consider local needs and challenges. number of clinical sites is expected to rapidly increase within the next few years. For the coming wave of new sites in China, strong partnerships/ collaborations with investigators and sites that enable them to deliver will be a key factor for success. In Japan, the challenges are different, and more similar to western countries. There is more competition for a limited patient pool and the population is shrinking. Frustration with the limitations to the current approaches is creating a market that is more and more open to new ideas. Data- driven feasibility is just beginning to gain acceptance and patient- centric approaches are also attracting attention. Such an environment requires innovative approaches and strategies, which are tailored to these markets. Keys to Innovation Innovations can come in the form of products and process improvements. Global innovation coupled with thoughtful local implementation is essential to succeed. To accomplish this, one needs to hire and develop the right talent, and work with the right partners, to foster innovations, develop them, and subsequently implement them in the best possible way. Local implementation of patient recruitment innovation requires knowledge of not only the challenges, but also the needs of the specific markets. Proof Point: National Cancer Centre Singapore (NCCS) In 2016, BMC Women’s Health published a study1 titled “Barriers and facilitators for clinical trial participation among diverse Asian patients with breast cancer: a qualitative study.” The study was conducted in the NCCS, which treats 75 per cent of cancer patients in Singapore and has a yearly outpatient 1 https://bmcwomenshealth.biomedcentral.com/ articles/10.1186/s12905-016-0319-1 Challenges for Different Geographies In Asia, there are challenges unique to the region for clinical trial recruitment, compared to the western world. For example, in China with a population of 1.4 billion people, the shortage is not in patients, but in site staff capable and experienced at delivering quality clinical trial results. On October 8 this year, the China Food and Drug Agency (CFDA) announced a new site certification process. Hospitals are now able to self-register as a clinical trial site, with the responsibility for qualifying such sites lying with the study sponsors. As a result, the
  • 30. 28 Pharma Focus Asia ISSUE - 29 2017 attendance of more than 130,000. In this study, various focus groups studied females over the age of 21 with breast cancer, who were able to provide informed consent and attend the focus group by themselves. The study examined the factors that influence patient recruitment into clinical trials in Asia, each factor showcasing an area of clinical trial recruitment with the potential to lessen the patient burden and improve the overall experience. These were found to include: 1. Knowledge and Attitude: Several patients in the study said they had not heard of the term “clinical trial,” and many that had heard of the term were previously or currently enrolled in one. This lack of familiarity would be a potential hurdle for recruiters, because patients would be less likely to seek out clinical trials if they had no concept of their existence. However, it turned out that 80 per cent of the participants asked for more information about clinical trials, showing that there is a desire for information, but inadequate means to obtain it. 2. Reasons to Join: This study highlighted the individual, medical and societal factors affecting the patient’s decision to participate in clinical trials. One deciding factor for some of the women in the study was how the study was introduced to them. The women preferred and were more trusting of studies that were introduced to them by their doctors–highlighting the need for clinical trials to work with local institutions and within the local Asian community to target potential patients. 3. Relaying the Information: Another important take away from the study is that many participants said simpler language and visual aids, such as recordings and pictures should be used to relay the ICFs (Informed Consent Forms) and other information regarding clinical trials – including promotion of other clinical trials. Recruiters need to simplify the information and tailor it to audiences to make it easier for the patient to understand. Clinical TriAls
  • 31. 29w w w . p h a r m a f o c u s a s i a . c o m AuthorBIO DavidYoshiiistheSeniorDirectorforGlobalSiteSolutions,covering feasibility, patient recruitment, site alliances, and other site related strategies for clients at PAREXEL International. His career spans over 20 years in drug development in various global leadership roles. He joined PAREXEL in 2011. Needs of Specific Markets: Getting the Word Out The study conducted by BMC Women’s Health shows there is an opportunity to improve how we approach clinical trials. The industry is rapidly embracing patient centric methodologies, as a means to improve the patient experience, with the potential to improve recruitment rates, increase compliance with study procedures and reduce withdrawals. Increasingly technologies such as “web listening” are being employed to more accurately analyse the sentiment of patients and caregivers, as well as identify key influencers related to a specific indication. For Asia, this requires adapting technology for local languages, as well as differences in social media preferences. This approach allows companies to fine tune their approaches to provide valuable information about the disease, therapies, as well as the availability of clinical trials. Needs of Specific Markets: The Clinical Site Investigator sites are critical to the success of any clinical trial. PAREXEL alone has value-driven partnerships with hundreds of clinical sites across the world, of which one in four sites are located in Asia, to support drug development for our clients’ investigational medicinal products. These sites, located in Japan, China, Korea, Taiwan, and in key countries throughout the rest of Asia, provide a means for patients to not only access innovative, new therapies, but have an improved clinical trial experience. Creating these partnerships in Asia is especially important for trial participation and diversity, as shown by the FDA in the 2015-2016 Global Participation in Clinical Trials Report where the majority of Asian trial participants in global studies were at non-US sites. Identifying the right sites isn’t easy. Data-driven feasibility is an approach to support site selection. Unfortunately, it is highly dependent on the robustness of the data being employed. For some countries, historical data is sometimes scarce, depending on the indication or drug’s mechanism of action. This entails augmentation, which requires tailoring the approach to what is optimal in the specific country. In Japan and China, collaborating with Site Management Organisations (SMOs) that provide study nurse dispatch services to clinical sites has proven effective, in addition to other country-specific approaches. Needs of Specific Markets: Relaying the Information Patient recruitment doesn’t end with identifying the patient, but requires the patient to consent to participate in the clinical trial. For the patient to give consent, they must first have a comprehensive understanding of the study. Some tools on the market try to make this information easily digestible with the use of animation to provide the patient with an overview of the study and related information – these tools are being actively used in China, Taiwan, Korea, and Japan. Such tools are often tailored culturally with voice overs in the local language and with animation that not only appeals to young children, but also adults and elderly patients, due to the ease of comprehension. There have already been increased trial consent rates, improved compliance /retention and shortened recruitment timelines in the studies where these tools have been implemented. An important factor is ensuring that the animation is culture agnostic and therefore acceptable in these very particular markets, and the simplicity of implementation is important to meet the needs of highly variable site environments. Reflections Approaches for patient recruitment must have one thing in common: they must make things simpler for the patient. Participating in a clinical trial is filled with anxiety and uncertainties, especially coupled with existing challenges from the underlying disease. Reducing the anxiety and clinical trial burden are obvious steps to make things simpler for the patient. The industry has decades and decades of experience in running clinical trials. However, as treatments continue to evolve, there is a need to advance the way we run the clinical trials, to not only provide evidence of efficacy and safety, but to also gain further insights into how we can provide additional value for patients and investigator sites. Innovations in patient recruitment coupled with thoughtful local implementation are a step forward in our relentless pursuit to simplify the patient journey. Local implementation of patient recruitment innovation requires knowledge of not only the challenges, but also the needs of the specific markets. Clinical TriAls
  • 32. 30 Pharma Focus Asia ISSUE - 29 2017 Clinical Trails
  • 33. 31w w w . p h a r m a f o c u s a s i a . c o m Landmark global XANTUS real-world programme showed low rates of stroke and major bleeding of 0.9 per cent and 1.7 per cent per year respectively with rivaroxaban, generally consistent with Phase III Rocket AF trial. John Battersby, Medical Writer, Bridges Publishing Pte Ltd Low Rates of Stroke and Major Bleeding with Rivaroxaban Confirmed by Global Study XANTUS pooled results study R esults of the pooled analysis of the global XANTUS real- world study programme were announced recently at the European Society of Cardiology (ESC) Congress in Barcelona, Spain.The study investigated the use of the non-vitamin K antagonist oral anticoagulant (NOAC) rivaroxaban for stroke prevention in patients with non-valvular Atrial Fibrillation (AF) (irregular heart beat). The study showed low rates of both stroke and major bleeding, including fatal intracranial (skull) bleeds in AF patients on Xarelto® for stroke prevention. The majority (96.1 per cent) of the pooled XANTUS population did not experience stroke / systemic embolism, major bleeding and all-cause death. This is generally consistent with the Phase III ROCKET AF trial and reaffirms the safety and efficacy of rivaroxaban in AF management. The global XANTUS programme is the largest prospective observational study on a single NOAC for stroke prevention in AF. This pooled analysis combined real-world data from three prospective, single-arm, multi-centre studies across multiple regions, which together followed more than 11,000 patients from 47 countries: 1. XANTUS, the largest of the studies, which followed 6,784 patients from Canada, Israel and 10 countries across Europe. Clinical TriAls
  • 34. 32 Pharma Focus Asia ISSUE - 29 2017 2. XANAP, the first Pan-Asian real- world study of rivaroxaban in AF stroke prevention, which followed 2,273 patients from 10 countries / territories in Asia (Hong Kong SAR, Indonesia, South Korea, Malaysia, Philippines, Singapore, Taiwan, Thailand, Vietnam and Pakistan). 3. XANTUS-EL which involved 2,101 patients from 17 countries in Eastern Europe, Middle East, Africa, and Latin America. Unmet Needs in Atrial Fibrillation (AF) AF is a heart condition characterised by irregular heartbeats which increases the risk of stroke caused by blood clots by five-fold. Strokes due to AF are also more severe, causing disability in over 50 per cent of patients and generally worse outcomes than strokes due to other causes. The incidence of AF increases with age. The prevalence of AF is a global issue with the number of AF patients growing rapidly and expected to have doubled by 2050. AF is especially of concern in Asia due the regions rapidly ageing populations. It is estimated that by 2050, Asia will have 72 million AF patients, and 2.9 million among them will suffer from an AF-associated stroke. The good news is AF-related strokes can be prevented. However, there is still a significant number of AF patients in Asia not receiving optimal anticoagulant therapy for stroke prevention. Older anticoagulant therapy with Vitamin K Antagonist (VKAs) such as warfarin makes effective anticoagulation harder for patients and physicians due to its manifold food and drug interactions, regular blood monitoring requirements and risk of intracranial (skull) bleeding. These serious disadvantages cause VKAs to be under-used or under-dosed in AF stroke prevention, leaving patients unprotected. “NOACs like rivaroxaban can potentially address this medical challenge as they are at least as effective as traditional warfarin therapy in preventing strokes in AF patients, but are easier to administer and carry a significantly lower risk of the life- threatening intracranial bleeding,” said Professor John Camm, the Professor of Clinical Cardiology at St George’s University of London who presented the results at ESC. “While this has been well proven in clinical trials and real-world studies, the consistency of the combined data from the worldwide XANTUS programme adds significantly to our understanding on the safety of NOACs in AF patients, and gives physicians the confidence to prescribe rivaroxaban in daily clinical practice.” The Studies In the XANTUS pooled analysis, a total of 11,121 patients were enrolled into the three real-world studies and included in the analysis. Patients were from 47 countries in Western Europe / Canada/ Israel (47.5 per cent), Eastern Europe (23.2 per cent), East Asia (20.1per cent), the Middle East/Africa (6.2 per cent) and Latin America (3.0 per cent). The major- ity of patients (73.1per cent) initially received rivaroxaban 20mg once daily, while 25.1 per cent, 1.6 per cent and 0.2 per cent of patients received rivaroxaban 15mg once daily, 10mg once daily and other doses, respectively. There were differences in patient demographics, Clinical TriAls
  • 35. 33w w w . p h a r m a f o c u s a s i a . c o m clinical characteristics as well as stroke and bleeding risks among the study regions. Patients with higher CHADS2 (stroke risk) or CHA2DS2-VASc (bleed- ing risk) scores at baseline were more likely to experience major bleeding, stroke /systemic embolism or death. Results from XANTUS pooled population showed low rates of both stroke and major bleeding with rivar- oxaban at 0.9 per cent and 1.7per cent per year respectively, generally consist- ent with those in the ROCKET AF trial. Mean CHADS2 (stroke risk) and CHA2DS2-VASc (bleeding risk) scores for the pooled population were 2.0 and 3.5 respectively. The findings were generally consistent across different regions and patient populations worldwide based on each of the individual studies. In XANAP, the Asian arm of XANTUS programme, the rates of both stroke and major bleeding were low at 1.7 per cent and 1.5 per cent respectively, generally consistent with Phase III ROCKET AF East Asia study and two other studies in the programme. CHADS2 (stroke risk) and CHA2DS2-VASc (bleeding risk) scores in XANAP were 2.3 and 3.7 respectively, higher than the mean scores of the XANTUS pooled population The majority (96.6 per cent) of patients on rivaroxaban in the study did not experience stroke / systemic embolism, major bleeding, and all-cause death. About XANTUS Pooled Analysis This is a pre-planned pooled analysis of the prospective, observational XANTUS, XANAP and XANTUS-EL studies of unselected patients with AF newly starting rivaroxaban for stroke prevention. Patients were followed for 1 year, at ~3-month intervals, or for ≥30 days after permanent discontinuation. Primary outcomes were major bleeding, Adverse Events (AEs) or Serious AEs (SAEs) and all-cause mortality. Secondary outcomes included symptomatic thromboembolic events and non-major bleeding. Treatment-emergent major outcomes were adjudicated by a central committee. 11,121 patients were included (Western Europe/Canada/ Israel: 47.5per cent; Eastern Europe: 23.2 per cent; East Asia: 20.1 per cent; Middle East and Africa: 6.2per cent; and Latin America: 3per cent). Of the patients 73.1per cent received rivaroxaban 20mg once daily (od) and 25.1per cent rivaroxaban 15mg (od); 72.4per cent had prior anticoagulation therapy. Mean age was 70.5 years and mean weight was 80.0kg.Co-morbidities included congestive heart failure (21.2per cent), hypertension (76.2per cent), diabetes mellitus (22.3per cent), prior stroke/non-central nervous system (CNS) systemic embolism (SE)/transient ischaemic attack (TIA; 21.3per cent) and prior myocardial infarction (MI; 8.9per cent). Rates of treatment-emergent major outcomes were: major bleeding 1.7 (1.5–2.0); all-cause mortality 1.9 (1.6–2.2); stroke/non-CNS SE 1.0 (0.8–1.2); stroke 0.9 (0.7–1.1). About XANAP XANAPis the first Pan-Asian, prospective, single-arm, observational study of 2,273 patients designed by Bayer to evaluate the safety and effectiveness of rivaroxaban for stroke prevention with non-valvular AF from 435 sites across Asia (Hong Kong SAR, Indonesia, South Korea, Malaysia, Philippines, The global XANTUS programme is the largest prospective observational study on a single NOAC for stroke prevention in AF. Clinical TriAls
  • 36. 34 Pharma Focus Asia ISSUE - 29 2017 AuthorBIO John has been science and technical writer for many years and has focused on medical and healthcare issues for more than a decade. He has spent the last 20 years in South East Asia, mainly based in Singapore, working as a freelance journalist and media adviser to the pharmaceutical industry. Singapore, Taiwan, Thailand, Vietnam and Pakistan) in routine clinical practice. All treatment and dosing decisions were at the discretion of the treating physicians and patients were followed up for one year or until 30 days after premature discontinuation. Bleeding events and major thromboembolic events were centrally adjudicated by an independent committee. At the end of the study, the majority (96.6 per cent) of patients on rivaroxaban did not experience stroke / systemic embolism, treatment- emergent major bleeding, and all-cause death. Overall, patients experienced treatment-emergent major bleeding at a rate of 1.5 per 100 patient-years (1.5 per cent per year); most of these major bleeds were treated using standard clinical measures. Rates of fatal bleeding were 0.2 per 100 patient-years 0.2 per cent per year). Critical organ bleeding occurred at a rate of 0.8 per 100 patient-years (0.8 per cent per year), which included intracranial bleeding at a rate of 0.7 per 100 patient-years (0.7 per cent per year). Stroke occurred at a rate of 1.7 per 100 patient-years (1.7per cent per year). The analyses from this study provide valuable insights on the usage of rivaroxaban by patients in Asia for non-valvular AF stroke prevention. “Strokes in AF patients are highly preventable. These robust findings further support rivaroxaban as a therapy of choice for stroke prevention in AF patients, with a low rate of major bleeding,” said Dr Foo Chuan Kit, Head of Medical Affairs of Bayer Pharmaceuticals Division for Asia- Pacific. “By involving Asian patients in this worldwide programme, we offer valuable insights to help physicians in the region safely and effectively lower the risk of stroke in their AF patients.” Latest ESC Guidelines NOACs are recommended as first-line anticoagulants in the prevention of AF-associated stroke in the latest international guidelines for the management of AF by the European Society of Cardiology (ESC). It is stated that NOACs offer better efficacy, safety and convenience compared with VKAs. NOACs are broadly preferable to VKAs in the vast majority of patients with AF. About Rivaroxaban Rivaroxaban is the world’s most widely prescribed NOAC that has been prescribed to 31 million patients worldwide and more than 3 million patients in Asia-Pacific for the management of blood clots in seven distinct indications, including stroke prevention in AF. Rivaroxaban is also the most broadly indicated NOAC, approved for seven indications, protecting patients across more venous and arterial thromboembolic conditions than any other NOAC: 1.The prevention of stroke and systemic embolism in adult patients with non-valvular AF with one or more risk factors 2.The treatment of Deep Vein Thrombosis (DVT) in adults 3.The treatment of Pulmonary Embolism (PE) in adults 4.The prevention of recurrent DVT and PE in adults 5.The prevention of Venous Thromboembolism (VTE) in adult patients under going elective hip replacement surgery 6. The prevention of VTE in adult patients undergoing elective knee replacement surgery 7. The prevention of atherothrombotic events (cardiovascular death, myocardial infarction or stroke) after an Acute Coronary Syndrome (ACS) in adult patients with elevated cardiac biomarkers and no prior stroke or transient ischaemic attack when co-administered with acetylsalicylic acid (ASA) alone or with ASA plusclopidogrel or ticlopidine. While regulatory approvals may differ from country to country, across all indications, rivaroxaban is approved in more than 130 countries. References are available at www. pharmafocusasia.com XANAP is the first Pan-Asian, prospective, single-arm, observational study of 2,273 patients designed by Bayer to evaluate the safety and effectiveness of rivaroxaban for stroke prevention with non-valvular AF from 435 sites across Asia. Clinical TriAls
  • 38. 36 Pharma Focus Asia ISSUE - 29 2017 W ith the demand for wearables and sensors in clinical trials on the rise, pharmaceutical companies are increasingly faced with the challenges of both rising costs and market saturation of similar drugs – and that is where Clinical Research Organisations (CROs) come into play. From both a technology perspective and a processes perspective, CROs can leverage remote medical devices, unleashing an opportunity to collect novel endpoints and supplemental data that may improve the regulatory case. This also opens the door for CROs to make the case for reimbursement more As real world evidence becomes an integral part for many clinical trials, wearables allow for monitoring and data collection anywhere the patient is located – freeing researchers of the location barrier of real world evidence. Xavier Flinois, President, PAREXEL Informatics Wearables in Clinical Trials Where we are & where we are going Clinical TriAls
  • 39. 37w w w . p h a r m a f o c u s a s i a . c o m compelling, open up trial participation to a wider population and/or reduce site visits for patients who may not live close to an investigative site. Although medical devices like spirometers and activity monitors have been used in clinical trials for almost a decade, modern wearable technology is improving the patient experience and lessening the data management burden. Outdated spirometers or activity monitors had to be transported back to the clinical site, where the data was then transcribed into an Electronic Data Capture (EDC) system, and downloaded – a process prone to transcription and human errors. Now wearables are more scalable and allow clinical sites to digitally collect the information without transporting or transcribing. These updates improve both trial efficiency and data accuracy. Regulating Medical Devices The use of medical devices for study endpoints has yet to receive regulatory guidance, but at a Drug Information Association Meeting in December 2016, the Federal Drug Administration (FDA) expressed cautious optimism that these devices could provide better and more timely insight into a patient’s health status. FDA speakers went so far as to say that researchers need not necessarily use medical devices with a 510(k) approval or CE stamp; consumer grade devices can be used as long as they are ‘fit for purpose.’ As regulators and drug companies accept the use of wearables, medical devices will play a more prominent role in clinical trial data collection, particularly in Phase II and III trials. Wearables by Phase: Phase I With the initial influx of information gathering in Phase I, wearables fit well into the protocol of the early clinical stage. One instance of this was a trial that added remote sensors into Phase I. The objective of adding this technology was to both pilot the new sensors as well as to compare the sensor data to the in-clinic data for a diabetes trial. With successful collaboration, the trial facilitators were able to produce a trial design that minimised the impact on the core protocol while maximising the number of devices. In all, six remote medical devices were added to the study –spirometer, blood pressure, pulse oximeter, blood glucose monitor, weight scale and activity monitor. Site and subject acceptance was high. It is expected that Sponsors developing new biologics where the benefit is best measured by sensors and/or where sensors provide valuable health status information to subjects, will begin piloting the applicable sensors in Phase I in parallel to their first in human clinical trials. Wearables by Phase: Phase II-III Because of the lack of regulatory guidance, the validated use of specific mobile health devices to deliver primary endpoint data is expected over the next 12–24 months. In Phase II and III trials, clinical trial sponsors will likely use medical devices as exploratory endpoints to mature their understanding of the utility of sensor- based endpoints. For some disorders, medical devices will be used across all phases as combination products. According to the FDA, “Combination products are therapeutic and diagnostic products that combine drugs, devices, and/or biological products. FDA expects to receive large numbers of combination products for review as technological advances continue to merge product types and blur the historical lines of separation between FDA’s medical product centers, which are made up of the Center for Biologics Evaluation and Research (CBER), the Center for Drug Evaluation and Research (CDER), and the Center for Devices and Radiological Health (CDRH).”11 Wearables by Phase: Phase IV The growing demand for wearables in clinical trials is also being seen in Phase IV studies. The post-marketing demands and remote connectivity make wearables an ideal Phase IV component. Sponsors have the opportunity to make a strong case to regulators, especially in regard to why certain drugs should move to an over-the-counter status since the general population has the ability to use commonly available medical devices to either self-diagnose or monitor a particular health condition. Thanks to the maturation of this technology medical devices can now securely and wirelessly transfer data, increasing the integrity of clinical trial data. For example, once a reading is taken on a blood pressure monitor, that data is automatically downloaded to a hub (a device plugged into an electrical outlet). The patient then plugs in the hub once and takes his or her readings on the prescribed schedule. All of the data transfer is handled seamlessly and securely without the need for manual intervention – reducing the chance of human error. If the patient forgets to plug in the hub, the data is stored on the medical device until it’s plugged in. Alternatively, there is an option to securely transfer data via a companion app on a smartphone. What Else can Wearables Enable? Medical devices offer a multitude of possibilities for researchers that go 1 “About Combination Products” - https://www.fda.gov/ CombinationProducts/AboutCombinationProducts Effective medical device use requires best-in-class medical, HEOR, biostatistics, logistics, technology and clinical trial conduct capabilities. Clinical TriAls
  • 40. 38 Pharma Focus Asia ISSUE - 29 2017 far beyond collecting blood pressure. Using the data collected from wearables, predictive analytics may allow medical devices to alert researchers of future medical events. The application of predictive analytics to connected medical device data may enable the identification of subjects who are who are not protocol compliant such that the sites can intervene to increase subject retention. A predictive analytics for sensor-based data will enable increased patient retention and safety. Wearables not only simplify data collection and improve patient safety; this technology allows for the advancement of international partnerships where multiple teams can be connected in real-time. Remote and in-clinic data can be “fused” together for sites and study teams to view side-by-side in Phase I-IV clinical trials. This takes away the barrier of geographic location for multiple sites working across the globe, and allowing this increased comparison of diverse data will increase the integrity of the results on an international scale. The value of wearables is not limited to trials sites. As Real World Evidence (RWE) becomes an integral part for many clinical trials, wearables allow for monitoring and data collection anywhere the patient is located – freeing researchers of the location barrier of RWE Wearables have created a structure where data collection is aboundary-free factor in clinical trial management. End-to-End Medical Device Components It is critical that Sponsors leverage a medical device solution that securely and wirelessly transmits the data with the ability to store, visualise and alert from the big data time series data; however, the application of medical devices is not just a technology exercise. The performance of medical devices must be evaluated prior to use for study endpoints to understand if the device generates data within acceptable parameters and in comparison to the manufacturer's claims. Informed Consent Forms must be adapted for the collection of personal data and there are data storage and data transmission/re-use implications, particularly in the European Union. There are health economic and outcomes research considerations that must be taken into account to ensure that the associated endpoints are fit for purpose for regulatory submissions. Logistics also plays an important role on the front end, when devices are acquired, kitted and distributed to sites in a timely manner that accommodates the storage limitation at the sites. At the end of a trial, the devices need to be returned; cleansed or destroyed; and all data deleted from the device. Effective medical device use requires best-in-class medical, HEOR, biostatistics, logistics, technology and clinical trial conduct capabilities. Where does this Go Next? So where can wearables take the industry? The shrinking size of medical devices and connected implantable device along with evolving technology will further enable the collection of novel and complementary data to support regulatory submissions and reimbursement. With experience and regulatory acceptance, the potential for connected medical devices is extraordinary. These devices have the potential to change the way clinical trials are conducted; to broaden participation in clinical trials at a time when subject recruitment is major barrier; to enable virtual trials; and to reduce clinical trial costs. The challenge today is not deciding on whether to use a mobile health device, but the effective integration into drug development programmes. AuthorBIO Xavier Flinois leads PAREXEL’s Informatics division, which provides innovative technology solutions to help optimise patient engagement, clinical and regulatory processes. He brings to PAREXEL more than 25 years of experience in technology and healthcare, including senior leadership positions with global companies in the clinical software, consulting and IT services areas. Clinical TriAls
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  • 42. 40 Pharma Focus Asia ISSUE - 29 2017 Technology transfer is not just limited to industries and R&D. A research scientist working in R&D may also work with universities. There are several examples of patent or product commercialisation happening in universities. This article focuses on how technology transfer can be coupled with knowledge translation. Vivek Dave, Sachdev Yadav, Harshavardhan ML Yadav, Isha Mehta Department of Pharmacy, Banasthali University Merging Technology Transfer with Knowledge Translation Academic to industrial research T he government and research academics are increasingly aware of the relevance of their result to the industrial sector. The term knowledge translation was coined to represent proactive strategies to communicate research findings to those in a position to put the findings into practice. As it happens in most cases, the first consideration is given to market size. Simply put, it means that the market where we are supposed to market the product should be large enough to trade it in a very big volume. Moreover, it is very important to see weather Research & Development
  • 43. 41w w w . p h a r m a f o c u s a s i a . c o m the intended result can be patentable or not, especially in the pharmaceutical industries. Technology transfer does not always involve a patentable invention, but also the transfer of the intact technology including copyrights, proficiency, and others. A good patent is that which cannot be overcome by any other universities; a weak patent will allow other universities or researchers to come up with good amendments on our idea leading to the problems of licensing. Some universities require employees and graduate students to report all inventions to the universities and, upon request, execute a formal assignment document. The Bayh Dole Act, a nonprofit organisational research and its documentation work that is closely concerned to the field, permits funding agencies to grant inventors requests to retain title, provided the universities have waived election of the title. However, if universities believe an invention is valuable, they will usually elect title, apply for patents, and then license the rights exclusively back to the inventors. This is the procedure usually followed in the case of inventors who obtain venture capital to form companies to develop their discoveries. However, a number of universities support their employees who wish to preserve the title to their inventions, and have sensible plans to ensure growth. Most universities also assert ownership over non patentable materials created by their employees and recorded information generated by their employees. The quality of industry technology transfers is based on the student and industry relationships. The interaction with industry can also educate faculty and students with regard to salaries and working conditions in industry. Students learn that scientists in industry also publish. They learn that scientists in industry can spend less time raising funds for their labs than those in academia. It also has the potential for educating them with regard to the rewards of working in industry. This interaction can go a long way towards ridding industry of the stigma that has caused it recruitment problems in the past. Technology transfer can also provide funds for students and resources for enhancing programmes. They set some goals for preparing and distributing technology transfer guidelines which are shown in figure 1. The Bayh Dole Act Providing the Platform for Universities Technology Transfer The Bayh Dole Act enacted on December 12, 1980 (The Patent & Trademark Act Amendments) (Public Law 96-517) created a uniform patent policy among federal agencies that fund research. Bayh-Dole enables small businesses and non-profit organisations, including universities, to retain title to materials and products they invent under federal funding. Subsequent amendments created uniform licensing guidelines and expanded the law to include all federally funded contractors (Public Law 98-620). The implementing regulations for Bayh-Dole are published at 37 CFR Part 401. Regulations Implementing Federal Patent and Licensing Policy Regarding ‘Rights to Inventions Made by Nonprofit Organisations, Universities and Small Business Firms’ are Codified at 37 Cfr Part 401. The Following Summarises the Significant Aspects of these Regulations • The provisions apply to all inventions conceived or first actually reduced to practice in the performance of a federal grant, contract, or cooperative agreement. This is true even if the federal government is not the sole source of funding for either the conception or the reduction to practice. The provisions do not, however, apply to federal grants that are primarily for the training of students and postdoctoral scientists • The university has an obligation to disclose each new invention to the federal funding agency within two months after the inventor discloses it in writing to the universities • The decision whether or not to retain title to the invention must be made within two years after disclosing the invention to the agency. This time may be shortened, if, due to publication of research results or public use, the one-year US statutory patent bar has been set in motion. Under such circumstances, the universities must make an election at least sixty days before the end of the statutory period. If the university does not elect to retain title, the agency may take title to the invention • Upon election of title, the universities must file a patent application within one year, or prior to the end of any Research & Development Figure 1 Goals for preparing and distributing technology transfer guidelines Defining Rights And Responsibilities Goals Revneu for the creator students Assisting students in commercialising their products Making inventions available tp all consumers